Drug Condensation Aerosols And Kits

ABSTRACT

The present invention provides novel condensation aerosols for the treatment of disease and/or intermittent or acute conditions. These condensation aerosols have little or no pyrolysis degradation products and are characterized by having an MMAD of between 1-3 microns. These aerosols are made by rapidly heating a substrate coated with a thin film of drug having a thickness of between 0.05 and 20 μm, while passing a gas over the film, to form particles of a desirable particle size for inhalation. Kits comprising a drug and a device for producing a condensation aerosol are also provided. The device contained in the kit typically, has an element for heating the drug which is coated as a film on the substrate and contains a therapeutically effective dose of a drug when the drug is administered in aerosol form, and an element allowing the vapor to cool to form an aerosol. Also disclosed, are methods for using these aerosols and kits.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/078,679, filed Nov. 13, 2013, entitled “Drug Condensation Aerosolsand Kits”, which is a continuation of U.S. patent application Ser. No.13/569,006, filed Aug. 7, 2012, entitled “Drug Condensation Aerosols AndKits,” which is a continuation of U.S. patent application Ser. No.12/117,737, filed May 8, 2008. U.S. patent application Ser. No.12/117,737, filed May 8, 2008, now U.S. Pat. No. 8,235,037, is acontinuation of U.S. patent application Ser. No. 11/504,419, entitled“Drug Condensation Aerosols and Kits”, filed Aug. 15, 2006.

U.S. patent application Ser. No. 11/504,419, filed Aug. 15, 2006 is acontinuation of U.S. patent application Ser. No. 10/718,982, entitled“Drug Condensation Aerosols and Kits”, filed Nov. 20, 2003, U.S. Pat.No. 7,090,830, issued Aug. 15, 2006.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isa continuation-in-part of application Ser. No. 10/057,197, filed Oct.26, 2001, U.S. Pat. No. 7,766,013, issued Aug. 3, 2010, which claimsbenefit of Provisional Application No. 60/296,225, filed Jun. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/057,198, filedOct. 26, 2001, which claims benefit of Provisional Application No.60/296,225, filed Jun. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/146,080, filedMay 13, 2002, U.S. Pat. No. 7,942,147, issued May 17, 2011, which is acontinuation-in-part of application Ser. No. 10/057,198, filed Oct. 26,2001, which claims the benefit of Provisional Application No.60/296,225, filed Jun. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/146,086, filedMay 13, 2002, U.S. Pat. No. 7,458,374, issued Dec. 2, 2008.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/146,088, filedMay 13, 2002, U.S. Pat. No. 7,537,009, issued May 26, 2009, which is acontinuation-in-part of patent application Ser. No. 10/057,198, filedOct. 26, 2001, which claims the benefit of Provisional Application No.60/296,225, filed Jun. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/146,515, filedMay 13, 2002, U.S. Pat. No. 6,682,716, issued Jan. 27, 2004, which is acontinuation-in-part of patent application Ser. No. 10/057,198, filedOct. 26, 2001, which claims the benefit of Provisional Application No.60/296,225, filed Jun. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/146,516, filedMay 13, 2002, U.S. Pat. No. 6,737,042, issued May 18, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and also claims the benefit of Provisional Application No.60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/150,056, filedMay 15, 2002, U.S. Pat. No. 6,805,853, issued Oct. 19, 2004, whichclaims the benefit of Provisional Application No. 60/345,882, filed Nov.9, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/150,267, filedMay 15, 2002, U.S. Pat. No. 6,797,259, issued Sep. 28, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/150,268, filedMay 15, 2002, U.S. Pat. No. 6,780,399, issued Aug. 24, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/150,591, filedMay 17, 2002, U.S. Pat. No. 6,780,400, issued Aug. 24, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/150,857, filedMay 17, 2002, U.S. Pat. No. 6,716,415, issued Apr. 6, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/151,596, filedMay 16, 2002, U.S. Pat. No. 6,855,310, issued Feb. 15, 2005, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/151,626, filedMay 16, 2002, U.S. Pat. No. 6,783,753, issued Aug. 31, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/152,639, filedMay 20, 2002, U.S. Pat. No. 6,716,416, issued Apr. 6, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/152,640, filedMay 20, 2002, U.S. Pat. No. 6,743,415, issued Jun. 1, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/152,652, filedMay 20, 2002, U.S. Pat. No. 6,740,307, issued May 25, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/153,139, filedMay 20, 2002, U.S. Pat. No. 6,814,954, issued Nov. 9, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/153,311, filedMay 21, 2002, U.S. Pat. No. 6,884,408, issued Apr. 26, 2005, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/153,313, filedMay 21, 2002, which claims the benefit of Provisional Application No.60/294,203, filed May 24, 2001, and of Provisional Application No.60/317,479, filed Sep. 5, 2001, and of Provisional Application No.60/345,145, filed Nov. 9, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/153,831, filedMay 21, 2002, U.S. Pat. No. 6,740,308, issued May 25, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/153,839, filedMay 21, 2002, U.S. Pat. No. 6,776,978, issued Aug. 17, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/154,594, filedMay 23, 2002, U.S. Pat. No. 6,740,309, issued May 25, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/154,765, filedMay 23, 2002, U.S. Pat. No. 6,814,955, issued Nov. 9, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/155,097, filedMay 23, 2002, U.S. Pat. No. 6,716,417, issued Apr. 6, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/155,373, filedMay 22, 2002, U.S. Pat. No. 6,737,043, issued May 18, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001,and of Provisional Application No. 60/345,876, filed Nov. 9, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/155,621, filedMay 22, 2002, U.S. Pat. No. 6,759,029, issued Jul. 6, 2004, which claimsthe benefit of Provisional Application No. 60/294,203, filed May 24,2001, and of Provisional Application No. 60/317,479, filed Sep. 5, 2001,and of Provisional Application No. 60/332,280, filed Nov. 21, 2001, andof Provisional Application No. 60/336,218, filed Oct. 30, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/155,703, filedMay 22, 2002, U.S. Pat. No. 6,803,031, issued Oct. 12, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/155,705, filedMay 22, 2002, U.S. Pat. No. 6,805,854, issued Oct. 19, 2004, whichclaims the benefit of Provisional Application No. 60/294,203, filed May24, 2001, and of Provisional Application No. 60/317,479, filed Sep. 5,2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/280,315, filedOct. 25, 2002, which claims the benefit of Provisional Application No.60/335,049, filed Oct. 30, 2001, and of Provisional Application No.60/371,457, filed Apr. 9, 2002.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/302,010, filedNov. 21, 2002, U.S. Pat. No. 7,078,016, issued Jul. 18, 2006, whichclaims the benefit of Provisional Application No. 60/332,279, filed Nov.21, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/302,614, filedNov. 21, 2002, which claims the benefit of Provisional Application No.60/332,165, filed Nov. 21, 2001.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/322,227, filedDec. 17, 2002, which claims the benefit of Provisional Application No.60/342,066, filed Dec. 18, 2001, and of Provisional Application No.60/412,068, filed Sep. 18, 2002.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/633,877 filedAug. 4, 2003, U.S. Pat. No. 7,585,493, issued Sep. 8, 2009.

U.S. patent application Ser. No. 10/718,982, U.S. Pat. No. 7,090,830, isalso a continuation-in-part of application Ser. No. 10/633,876 filedAug. 4, 2003, U.S. Pat. No. 7,645,442, issued Jan. 12, 2010.

All of the applications cited above are incorporated by reference intheir entirety. Any disclaimer that may have occurred during theprosecution of the above-referenced application(s) is hereby expresslyrescinded, and reconsideration of all relevant art is respectfullyrequested.

FIELD OF THE INVENTION

The present invention relates generally to the field of drug aerosolsand kits for delivering drug aerosols. More specifically, the inventionrelates to a condensation drug aerosol where the drug itself isvaporized.

BACKGROUND

There are a number of drug compositions commercially available for thetreatment of disease. These drugs are most commonly delivered as an oraldosage form (e.g. as a pill, capsule, or tablet), or deliveredintravenously. Disadvantages of oral dosage forms include a delay in theonset of activity and loss of drug therapeutic effect due to hepaticfirst-pass metabolism. Intravenous delivery, while typically moreeffective than oral delivery, is often painful and inconvenient. Thusother dosage forms and routes of administration with improved propertiesare desirable.

One such alternative is inhalation therapy. Many preclinical andclinical studies with inhaled compounds have demonstrated that efficacycan be achieved both within the lungs and systemically. Moreover, thereare many advantages associated with pulmonary delivery including rapidonset, the convenience of patient self-administration, the potential forreduced drug side-effects, ease of delivery by inhalation, theelimination of needles, and the like. Yet, in spite of these advantages,pulmonary delivery through inhalation therapy has played a relativelyminor role in the administration of therapeutic agents when compared tomore traditional drug administration routes of oral delivery anddelivery via injection.

The role of inhalation therapy in the health care field has remainedlimited mainly to treatment of asthma, in part due to a set of problemsunique to the development of inhalable drug formulations, especiallyformulations for systemic delivery by inhalation. Inhalation aerosolsfrom dry powder inhalers, nebulizers, and pressurized metered doseinhalers typically include excipients or solvents to increase stabilityor deliverability of these drugs in an aerosol form. Additionally,control of the particle size of these drug aerosols is challenging anddepends on the method used to form the aerosol and the other excipientsadded.

For example, when using dry powder inhalers (DPI's), the need to millthe drug to obtain an acceptable particle size for delivery to the lungsis problematic. Some mills used for micronization are known to produceheat, which can cause degradation of the drug if prolonged, and tend toshed metallic particles as contaminants. Moreover, as dry powderformulations are prone to aggregation and low flowability which canresult in diminished efficiency, scrupulous attention is required duringmilling, blending, powder flow, filling and even administration toensure that the dry powder aerosols are reliably delivered and have theproper particle size distribution for delivery to the lungs.

Nebulizers generate an aerosol from a liquid, some by breakup of aliquid jet and some by ultrasonic vibration of the liquid with orwithout a nozzle. All liquid aerosol devices must overcome the problemsassociated with formulation of the compound into a stable liquid state.Liquid formulations must be prepared and stored under aseptic or sterileconditions since they can harbor microorganisms. This necessitates theuse of preservatives or unit dose packaging. Additionally solvents,detergents and other agents are used to stabilize the drug formulation.

Pressurized metered dose inhalers, or pMDIs, are an additional class ofaerosol dispensing devices. pMDI's package the compound in a canisterunder pressure with a solvent and propellant mixture, usuallychlorofluorocarbons (CFC's,), or hydroflouroalkanes (HFA's). Upon beingdispensed a jet of the mixture is ejected through a valve and nozzle andthe propellant “flashes off” leaving an aerosol of the compound. WithpMDI's particle size is hard to control and has poor reproducibilityleading to uneven and unpredictable bioavailability. Moreover, due tothe high speed ejection of the aerosol from the nozzle, pMDIs deliverdrug inefficiently as much of the drug impacts ballistically on thetongue, mouth and throat and never gets to the lung.

Thus, there remains a need for methods to prepare aerosols that arereadily deliverable and have minimal formulation issues. One such methodis to deliver drugs via vaporatization.

When using vaporization to form an aerosol, controlling a compound'sdegradation and anticipating the energies which activate thermaldegradation are typically very difficult. Activation energies of thesereactions depend on molecular structures, energy transfer mechanisms,transitory configurations of the reacting molecular complexes, and theeffects of neighboring molecules. Thus, while vaporization followed bycondensation of the vapor to form an aerosol provides a possiblemechanism to eliminate the need for costly formulations, which includeexcipients and other materials that are likely to change thepharmcokinetics and bioavailability of a drug, the challenge of usingthis technique for generating drug aerosols resides in the ability tocontrol thermal degradation during the vaporization step.

The present invention overcomes the foregoing discussed disadvantagesand problems with other inhalation technologies and provides a mechanismto control thermal degradation during vaporization making it possible toproduce pure aerosols of organic compounds without the need forexcipients or other additives, including solvents, wherein the particlesize is stable and selectable.

SUMMARY

In one aspect, the invention provides novel composition for delivery ofa drug comprising a condensation aerosol formed by volatilizing a heatstable drug composition under conditions effective to produce a heatedvapor of said drug composition and condensing the heated vapor of thedrug composition to form condensation aerosol particles, wherein saidcondensation aerosol particles are characterized by less than 10% drugdegradation products, and wherein the aerosol MMAD is less than 3microns.

In some variations, the aerosol comprises at least 50% by weight of drugcondensation particles. In other variations the aerosol comprises atleast 90% or 95% by weight of the drug condensation particles.Similarly, in some variations, the aerosol is substantially free ofthermal degradation products, and in some variations, the condensationaerosol has a MMAD in the range of 1-3 μm. In certain embodiments, theparticles have an MMAD of less than 5 microns, preferably less than 3microns. Preferably, the particles have a mass median aerodynamicdiameter of from 0.2 to 5 microns, or most preferably from 0.2 to 3microns. Also, in some variations the molecular weight of the compoundis typically between 200 and 700. Typically, the aerosol comprises atherapeutically effective amount of drug and in some variations maycomprise pharmaceutically acceptable excipients. In some variations, thecarrier gas is air. In some variations, other gases or a combination ofvarious gases may be used.

In another aspect of the invention, the invention provides compositionsfor inhalation therapy, comprising an aerosol of vaporized drugcondensed into particles, characterized by less than 5% drug degradationproducts, and wherein said aerosol has a mass median aerodynamicdiameter between 1-3 microns.

In some variations of the aerosol compositions, the carrier gas is anon-propellant, non-organic solvent carrier gas. In other variations,the aerosol is substantially free of organic solvents and propellants.

In yet other embodiments, aerosols of a therapeutic drug are providedthat contain less than 5% drug degradation products, and a mixture of acarrier gas and condensation particles, formed by condensation of avapor of the drug in said carrier gas; where the MMAD of the aerosolincreases over time, within the size range of 0.01 to 3 microns as saidvapor cools by contact with the carrier gas.

In some variations, the aerosol comprises at least 50% by weight of drugcondensation particles. In other variations the aerosol comprises atleast 90% or 95% by weight of the drug condensation particles. In somevariations, the MMAD of the aerosol is less than 1 micron and increasesover time. Also, in some variations the molecular weight of the compoundis typically between 200 and 700. In other variations, the compound hasa molecular weight of greater than 350 and is heat stable. Typically,the aerosol comprises a therapeutically effective amount of drug and insome variations may comprise pharmaceutically acceptable excipients. Insome variations, the carrier gas is air. In some variations, other gasesor a combination of various gases may be used.

The condensation aerosols of the various embodiments are typicallyformed by preparing a film containing a drug composition of a desiredthickness on a heat-conductive and impermeable substrate and heatingsaid substrate to vaporize said film, and cooling said vapor therebyproducing aerosol particles containing said drug composition. Rapidheating in combination with the gas flow helps reduce the amount ofdecomposition. Thus, a heat source is used that typically heats thesubstrate to a temperature of greater than 200° C., preferably at least250° C., more preferably at least 300° C. or 350° C. and producessubstantially complete volatilization of the drug composition from thesubstate within a period of 2 seconds, preferably, within 1 second, andmore preferably, within 0.5 seconds.

Typically, the gas flow rate over the vaporizing comound is betweenabout 4 and 50 L/minute.

The film thickness is such that an aerosol formed by vaporizing thecompound by heating the substrate and condensing the vaporized compoundcontains 10% by weight or less drug-degradation product. The use of thinfilms allows a more rapid rate of vaporization and hence, generally,less thermal drug degradation. Typically, the film has a thicknessbetween 0.05 and 20 microns. In some variations, the film has athickness between 0.5 and 5 microns. The selected area of the substratesurface expanse is such as to yield an effective human therapeutic doseof the drug aerosol.

Exemplary compounds for use in the invention, and corresponding filmthickness ranges are:

-   -   alprazolam, film thickness between 0.1 and 10 μm;    -   amoxapine, film thickness between 2 and 20 μm;    -   atropine, film thickness between 0.1 and 10 μm;    -   bumetanide film thickness between 0.1 and 5 μm;    -   buprenorphine, film thickness between 0.05 and 10 μm;    -   butorphanol, film thickness between 0.1 and 10 μm;    -   clomipramine, film thickness between 1 and 8 μm;    -   donepezil, film thickness between 1 and 10 μm;    -   hydromorphone, film thickness between 0.05 and 10 μm;    -   loxapine, film thickness between 1 and 20 μm;    -   midazolam, film thickness between 0.05 and 20 μm;    -   morphine, film thickness between 0.2 and 10 μm;    -   nalbuphine, film thickness between 0.2 and 5 μm;    -   naratriptan, film thickness between 0.2 and 5 μm;    -   olanzapine, film thickness between 1 and 20 μm;    -   paroxetine, film thickness between 1 and 20 μm;    -   pramipexole, film thickness between 0.05 and 10 μm;    -   prochlorperazine, film thickness between 0.1 and 20 μm;    -   quetiapine, film thickness between 1 and 20 μm;    -   rizatriptan, film thickness between 0.2 and 20 μm;    -   sertraline, film thickness between 1 and 20 μm;    -   sibutramine, film thickness between 0.5 and 2 μm;    -   sildenafil, film thickness between 0.2 and 3 μm;    -   sumatriptan, film thickness between 0.2 and 6 μm;    -   tadalafil, film thickness between 0.2 and 5 μm;    -   vardenafil, film thickness between 0.1 and 2 μm;    -   venlafaxine, film thickness between 2 and 20 μm;    -   zolpidem, film thickness between 0.1 and 10 μm;    -   apomorphine HCl, film thickness between 0.1 and 5 μm;    -   celecoxib, film thickness between 2 and 20 μm;    -   ciclesonide, film thickness between 0.05 and 5 μm;    -   eletriptan, film thickness between 0.2 and 20 μm;    -   parecoxib, film thickness between 0.5 and 2 μm;    -   valdecoxib, film thickness between 0.5 and 10 μm;    -   fentanyl, film thickness between 0.05 and 5 μm;    -   citalopram, film thickness between 1 and 20 μm;    -   escitalopram, film thickness between 0.2 and 20 μm;    -   clonazepam, film thickness between 0.05 and 8 μm;    -   oxymorphone, film thickness between 0.1 and 10 μm;    -   albuterol, film thickness between 0.2 and 2 μm;    -   sufentanyl, film thickness between 0.05 and 5 μm; and    -   remifentanyl, film thickness between 0.05 and 5 μm.

In a related aspect, the invention includes kits for delivering a drugcondensation aerosol that typically comprises a composition devoid ofsolvents and excipients and comprising a heat stable drug, and a devicefor forming and delivering via inhalation a condensation aerosol. Thedevice for forming a drug aerosol typically comprises an elementconfigured to heat the composition to form a vapor, an element allowingthe vapor to condense to form a condensation aerosol, and an elementpermitting a user to inhale the condensation aerosol. Typically, theelement configured to heat the composition comprises a heat-conductivesubstrate and formed on the substrate is typically a drug compositionfilm containing a therapeutically effective dose of a drug when the drugis administered in an aerosol form. A heat source in the device isoperable to supply heat to the substrate to produce a substratetemperature, typically that is greater than 300° C., to substantiallyvolatilize the drug composition film from the substrate in a period of 2seconds or less, more preferably, in a period of 500 milliseconds orless. The device may further comprise features such as breath-actuationor lockout elements.

In yet another aspect of the invention kits are provided for deliveringa drug aerosol comprising a thin film of a drug composition and a devicefor dispensing said film as a condensation aerosol. Typically, the filmthickness is between 0.5 and 20 microns. The film can comprisepharmaceutically acceptable excipients and is typically heated at a rateso as to substantially volatilize the film in 500 milliseconds or less.

These and other objects and features of the invention will be more fullyappreciated when the following detailed description of the invention isread in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B are cross-sectional views of general embodiments of adrug-supply article in accordance with the invention;

FIG. 2A is a perspective view of a drug-delivery device thatincorporates a drug-supply article;

FIG. 2B shows another drug-delivery device that incorporates adrug-supply article, where the device components are shown inunassembled form;

FIGS. 3A-3E are high-speed photographs showing the generation of aerosolparticles from a drug-supply unit;

FIGS. 4A-4B are plots of substrate temperature increase, measured instill air with a thin thermocouple (Omega, Model CO2-K), as a functionof time. The substrate in FIG. 4A was heated resistively by connectionto a capacitor charged to 13.5 Volts (lower line), 15 Volts (middleline), and 16 Volts (upper line); the substrate in FIG. 4B was heatedresistively by discharge of a capacitor at 16 Volts;

FIGS. 5A-5B are plots of substrate temperature, in ° C., as a functionof time, in seconds, for a hollow stainless steel cylindrical substrateheated resistively by connection to a capacitor charged to 21 Volts,where FIG. 5A shows the temperature profile over a 4 second time periodand FIG. 5B is a detail showing the temperature profile over the firstsecond of heating;

FIG. 6 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for the drug atropine free base;

FIG. 7 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for donepezil free base;

FIG. 8 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for hydromorphone free base;

FIG. 9 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for buprenorphine free base;

FIG. 10 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for clomipramine free base;

FIG. 11 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for ciclesonide;

FIG. 12 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for midazolam free base;

FIG. 13 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for nalbuphine free base;

FIG. 14 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for naratriptan free base;

FIG. 15 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for olanzapine free base;

FIG. 16 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for quetiapine free base;

FIG. 17 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for tadalafil free base;

FIG. 18 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for prochlorperazine free base;

FIG. 19 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for zolpidem free base;

FIG. 20 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for fentanyl free base;

FIG. 21 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for alprazolam free base;

FIG. 22 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for sildenafil free base;

FIG. 23 is plot showing purity of thermal vapor as a function of drugfilm thickness, in micrometers, for albuterol free base;

FIGS. 24A-24D are high speed photographs showing the generation of athermal vapor of phenytoin from a film of drug coated on a substratedrug-supply unit, where the photographs are taken prior to substrateheating (t=0 ms, FIG. 24A) and during substrate heating at times of 50milliseconds (FIG. 24B), 100 milliseconds (FIG. 24C), and 200milliseconds (FIG. 24D);

FIGS. 25A-25D are high speed photographs showing the generation of athermal vapor of disopyramide from a film of drug coated on a substratedrug-supply unit, where the photographs are taken at prior to substrateheating (t=0 ms, FIG. 25A) and during substrate heating at times of 50milliseconds (FIG. 25B), 100 milliseconds (FIG. 25C), and 200milliseconds (FIG. 25D); and

FIGS. 26A-26E are high speed photographs showing the generation of athermal vapor of buprenorphine from a film of drug coated on a substratedrug-supply unit, where the photographs are taken at prior to substrateheating (t=0 ms, FIG. 26A) and during substrate heating at times of 50milliseconds (FIG. 26B), 100 milliseconds (FIG. 26C), 200 milliseconds(FIG. 26D), and 300 milliseconds (FIG. 26E).

FIG. 27 is an illustration of an exemplary device that may be used toform and administer the aerosols described herein.

DETAILED DESCRIPTION Definitions

As defined herein, the following terms shall have the following meaningswhen reference is made to them throughout the specification.

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a collection of solid or liquid particles suspendedin a gas.

“Aerosol mass concentration” refers to the mass of particulate matterper unit volume of aerosol.

“Condensation aerosol” refers to an aerosol that has been formed by thevaporization of a composition and subsequent cooling of the vapor, suchthat the vapor condenses to form particles.

“Decomposition index” refers to a number derived from an assay describedin Example 238. The number is determined by subtracting the purity ofthe generated aerosol, expressed as a fraction, from 1.

“Drug” means any substance that is used in the prevention, diagnosis,alleviation, treatment or cure of a condition. The drug is preferably ina form suitable for thermal vapor delivery, such as an ester, free acid,or free base form. The drugs are preferably other than recreationaldrugs. More specifically, the drugs are preferably other thanrecreational drugs used for non-medicinal recreational purposes, e.g.,habitual use to solely alter one's mood, affect, state of consciousness,or to affect a body function unnecessarily, for recreational purposes.The terms “drug”, “compound”, and “medication” are used hereininterchangeably.

“Drug composition” refers to a composition that comprises only puredrug, two or more drugs in combination, or one or more drugs incombination with additional components. Additional components caninclude, for example, pharmaceutically acceptable excipients, carriers,and surfactants.

“Drug degradation product” or “thermal degradation product” are usedinterchangeably and means any byproduct, which results from heating thedrug(s) and is not responsible for producing a therapeutic effect.

“Drug supply article” or “drug supply unit” are used interchangeably andrefers to a substrate with at least a portion of its surface coated withone or more drug compositions. Drug supply articles of the invention mayalso include additional elements such as, for example, but notlimitation, a heating element.

“Fraction drug degradation product” refers to the quantity of drugdegradation products present in the aerosol particles divided by thequantity of drug plus drug degradation product present in the aerosol,i.e. (sum of quantities of all drug degradation products present in theaerosol)/((quantity of drug(s) present in the aerosol)+(sum ofquantities of all drug degradation products present in the aerosol)).The term “percent drug degradation product” as used herein refers to thefraction drug degradation product multiplied by 100%, whereas “purity”of the aerosol refers to 100% minus the percent drug degradationproducts.

“Heat stable drug” refers to a drug that has a TSR≧9 when vaporized froma film of some thickness between 0.05 μm and 20 μm. A determination ofwhether a drug classifies as a heat stable drug can be made as describedin Example 237.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Number concentration” refers to the number of particles per unit volumeof aerosol.

“Purity” as used herein, with respect to the aerosol purity, means thefraction of drug composition in the aerosol/the fraction of drugcomposition in the aerosol plus drug degradation products. Thus purityis relative with regard to the purity of the starting material. Forexample, when the starting drug or drug composition used for substratecoating contained detectable impurities, the reported purity of theaerosol does not include those impurities present in the startingmaterial that were also found in the aerosol, e.g., in certain cases ifthe starting material contained a 1% impurity and the aerosol was foundto contain the identical 1% impurity, the aerosol purity maynevertheless be reported as >99% pure, reflecting the fact that thedetectable 1% purity was not produced during thevaporization-condensation aerosol generation process.

“Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

“Support” refers to a material on which the composition is adhered,typically as a coating or thin film. The term “support” and “substrate”are used herein interchangeably.

“Substantially free of” means that the material, compound, aerosol,etc., being described is at least 95% free of the other component fromwhich it is substantially free.

“Typical patient tidal volume” refers to 1 L for an adult patient and 15mL/kg for a pediatric patient.

“Therapeutically effective amount” means the amount required to achievea therapeutic effect. The therapeutic effect could be any therapeuticeffect ranging from prevention, symptom amelioration, symptom treatment,to disease termination or cure.

“Thermal stability ratio” or “TSR” means the % purity/(100%-% purity) ifthe % purity is <99.9%, and 1000 if the % purity is ≧99.9%. For example,a respiratory drug vaporizing at 90% purity would have a TSR of 9. Anexample of how to determine whether a respiratory drug is heat stable isprovided in Example 237.

“4 μm thermal stability ratio” or “4TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 4 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 4-micron thick drug film is heated toaround 350° C. but not less than 200° C. for around 1 second to vaporizeat least 50% of the drug in the film.

“1.5 μm thermal stability ratio” or “1.5TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 1.5 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 1.5-micron thick drug film is heatedto around 350° C. but not less than 200° C. for around 1 second tovaporize at least 50% of the drug in the film.

“0.5 μm thermal stability ratio” or “0.5TSR” means the TSR of a drugdetermined by heating a drug-comprising film of about 0.5 microns inthickness under conditions sufficient to vaporize at least 50% of thedrug in the film, collecting the resulting aerosol, determining thepurity of the aerosol, and using the purity to compute the TSR. In suchvaporization, generally the about 0.5-micron thick drug film is heatedto around 350° C. but not less than 200° C. for around 1 second tovaporize at least 50% of the drug in the film.

“Vapor” refers to a gas, and “vapor phase” refers to a gas phase. Theterm “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

Aerosol Composition

The compositions described herein typically comprise at least one drugcompound. The drug compositions may comprise other compounds as well.For example, the composition may comprise a mixture of drug compounds, amixture of a drug compound and a pharmaceutically acceptable excipient,or a mixture of a drug compound with other compounds having useful ordesirable properties. The composition may comprise a pure drug compoundas well. In preferred embodiments, the composition consists essentiallyof pure drug and contains no propellants or solvents.

Any suitable drug compound may be used. Drugs that can be used include,for example but not limitation, drugs of one of the following classes:anesthetics, anticonvulsants, antidepressants, antidiabetic agents,antidotes, antiemetics, antihistamines, anti-infective agents,antineoplastics, antiparkisonian drugs, antirheumatic agents,antipsychotics, anxiolytics, appetite stimulants and suppressants, bloodmodifiers, cardiovascular agents, central nervous system stimulants,drugs for Alzheimer's disease management, drugs for cystic fibrosismanagement, diagnostics, dietary supplements, drugs for erectiledysfunction, gastrointestinal agents, hormones, drugs for the treatmentof alcoholism, drugs for the treatment of addiction, immunosuppressives,mast cell stabilizers, migraine preparations, motion sickness products,drugs for multiple sclerosis management, muscle relaxants, nonsteroidalanti-inflammatories, opioids, other analgesics and stimulants, opthalmicpreparations, osteoporosis preparations, prostaglandins, respiratoryagents, sedatives and hypnotics, skin and mucous membrane agents,smoking cessation aids, Tourette's syndrome agents, urinary tractagents, and vertigo agents.

Typically, where the drug is an anesthetic, it is selected from one ofthe following compounds: ketamine and lidocaine.

Typically, where the drug is an anticonvulsant, it is selected from oneof the following classes: GABA analogs, tiagabine, vigabatrin;barbiturates such as pentobarbital; benzodiazepines such as clonazepam;hydantoins such as phenytoin; phenyltriazines such as lamotrigine;miscellaneous anticonvulsants such as carbamazepine, topiramate,valproic acid, and zonisamide.

Typically, where the drug is an antidepressant, it is selected from oneof the following compounds: amitriptyline, amoxapine, benmoxine,butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine,kitanserin, lofepramine, medifoxamine, mianserin, maprotoline,mirtazapine, nortriptyline, protriptyline, trimipramine, venlafaxine,viloxazine, citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine,milnacipran, nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, escitalopram,tofenacin, trazodone, tryptophan, and zalospirone.

Typically, where the drug is an antidiabetic agent, it is selected fromone of the following compounds: pioglitazone, rosiglitazone, andtroglitazone.

Typically, where the drug is an antidote, it is selected from one of thefollowing compounds: edrophonium chloride, flumazenil, deferoxamine,nalmefene, naloxone, and naltrexone.

Typically, where the drug is an antiemetic, it is selected from one ofthe following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron, droperidol,granisetron, hyoscine, lorazepam, dronabinol, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domperidone, and palonosetron.

Typically, where the drug is an antihistamine, it is selected from oneof the following compounds: astemizole, azatadine, brompheniramine,carbinoxamine, cetrizine, chlorpheniramine, cinnarizine, clemastine,cyproheptadine, dexmedetomidine, diphenhydramine, doxylamine,fexofenadine, hydroxyzine, loratidine, promethazine, pyrilamine andterfenidine.

Typically, where the drug is an anti-infective agent, it is selectedfrom one of the following classes: antivirals such as efavirenz; AIDSadjunct agents such as dapsone; aminoglycosides such as tobramycin;antifungals such as fluconazole; antimalarial agents such as quinine;antituberculosis agents such as ethambutol; β-lactams such ascefmetazole, cefazolin, cephalexin, cefoperazone, cefoxitin,cephacetrile, cephaloglycin, cephaloridine; cephalosporins, such ascephalosporin C, cephalothin; cephamycins such as cephamycin A,cephamycin B, and cephamycin C, cephapirin, cephradine; leprostaticssuch as clofazimine; penicillins such as ampicillin, amoxicillin,hetacillin, carfecillin, carindacillin, carbenicillin, amylpenicillin,azidocillin, benzylpenicillin, clometocillin, cloxacillin, cyclacillin,methicillin, nafcillin, 2-pentenylpenicillin, penicillin N, penicillinO, penicillin S, penicillin V, dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin; quinolones such as ciprofloxacin,clinafloxacin, difloxacin, grepafloxacin, norfloxacin, ofloxacine,temafloxacin; tetracyclines such as doxycycline and oxytetracycline;miscellaneous anti-infectives such as linezolide, trimethoprim andsulfamethoxazole.

Typically, where the drug is an anti-neoplastic agent, it is selectedfrom one of the following compounds: droloxifene, tamoxifen, andtoremifene.

Typically, where the drug is an antiparkisonian drug, it is selectedfrom one of the following compounds: amantadine, baclofen, biperiden,benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa,carbidopa, andropinirole, apomorphine, benserazide, bromocriptine,budipine, cabergoline, eliprodil, eptastigmine, ergoline, galanthamine,lazabemide, lisuride, mazindol, memantine, mofegiline, pergolide,piribedil, pramipexole, propentofylline, rasagiline, remacemide,ropinerole, selegiline, spheramine, terguride, entacapone, andtolcapone.

Typically, where the drug is an antirheumatic agent, it is selected fromone of the following compounds: diclofenac, hydroxychloroquine andmethotrexate.

Typically, where the drug is an antipsychotic, it is selected from oneof the following compounds: acetophenazine, alizapride, amisulpride,amoxapine, amperozide, aripiprazole, benperidol, benzquinamide,bromperidol, buramate, butaclamol, butaperazine, carphenazine,carpipramine, chlorpromazine, chlorprothixene, clocapramine, clomacran,clopenthixol, clospirazine, clothiapine, clozapine, cyamemazine,droperidol, flupenthixol, fluphenazine, fluspirilene, haloperidol,loxapine, melperone, mesoridazine, metofenazate, molindrone, olanzapine,penfluridol, pericyazine, perphenazine, pimozide, pipamerone,piperacetazine, pipotiazine, prochlorperazine, promazine, quetiapine,remoxipride, risperidone, sertindole, spiperone, sulpiride,thioridazine, thiothixene, trifluperidol, triflupromazine,trifluoperazine, ziprasidone, zotepine, and zuclopenthixol.

Typically, where the drug is an anxiolytic, it is selected from one ofthe following compounds: alprazolam, bromazepam, oxazepam, buspirone,hydroxyzine, mecloqualone, medetomidine, metomidate, adinazolam,chlordiazepoxide, clobenzepam, flurazepam, lorazepam, loprazolam,midazolam, alpidem, alseroxlon, amphenidone, azacyclonol, bromisovalum,captodiamine, capuride, carbcloral, carbromal, chloral betaine,enciprazine, flesinoxan, ipsapiraone, lesopitron, loxapine,methaqualone, methprylon, propanolol, tandospirone, trazadone,zopiclone, and zolpidem.

Typically, where the drug is an appetite stimulant, it is dronabinol.

Typically, where the drug is an appetite suppressant, it is selectedfrom one of the following compounds: fenfluramine, phentermine andsibutramine.

Typically, where the drug is a blood modifier, it is selected from oneof the following compounds: cilostazol and dipyridamol.

Typically, where the drug is a cardiovascular agent, it is selected fromone of the following compounds: benazepril, captopril, enalapril,quinapril, ramipril, doxazosin, prazosin, clonidine, labetolol,candesartan, irbesartan, losartan, telmisartan, valsartan, disopyramide,flecanide, mexiletine, procainamide, propafenone, quinidine, tocainide,amiodarone, dofetilide, ibutilide, adenosine, gemfibrozil, lovastatin,acebutalol, atenolol, bisoprolol, esmolol, metoprolol, nadolol,pindolol, propranolol, sotalol, diltiazem, nifedipine, verapamil,spironolactone, bumetanide, ethacrynic acid, furosemide, torsemide,amiloride, triamterene, and metolazone.

Typically, where the drug is a central nervous system stimulant, it isselected from one of the following compounds: amphetamine, brucine,caffeine, dexfenfluramine, dextroamphetamine, ephedrine, fenfluramine,mazindol, methyphenidate, pemoline, phentermine, sibutramine, andmodafinil.

Typically, where the drug is a drug for Alzheimer's disease management,it is selected from one of the following compounds: donepezil,galanthamine and tacrin.

Typically, where the drug is a drug for cystic fibrosis management, itis selected from one of the following compounds: CPX, IBMX, XAC andanalogues; 4-phenylbutyric acid; genistein and analogous isoflavones;and milrinone.

Typically, where the drug is a diagnostic agent, it is selected from oneof the following compounds: adenosine and aminohippuric acid.

Typically, where the drug is a dietary supplement, it is selected fromone of the following compounds: melatonin and vitamin-E.

Typically, where the drug is a drug for erectile dysfunction, it isselected from one of the following compounds: tadalafil, sildenafil,vardenafil, apomorphine, apomorphine diacetate, phentolamine, andyohimbine.

Typically, where the drug is a gastrointestinal agent, it is selectedfrom one of the following compounds: loperamide, atropine, hyoscyamine,famotidine, lansoprazole, omeprazole, and rebeprazole.

Typically, where the drug is a hormone, it is selected from one of thefollowing compounds: testosterone, estradiol, and cortisone.

Typically, where the drug is a drug for the treatment of alcoholism, itis selected from one of the following compounds: naloxone, naltrexone,and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it isbuprenorphine.

Typically, where the drug is an immunosupressive, it is selected fromone of the following compounds: mycophenolic acid, cyclosporin,azathioprine, tacrolimus, and rapamycin.

Typically, where the drug is a mast cell stabilizer, it is selected fromone of the following compounds: cromolyn, pemirolast, and nedocromil.

Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

Typically, where the drug is a motion sickness product, it is selectedfrom one of the following compounds: diphenhydramine, promethazine, andscopolamine.

Typically, where the drug is a drug for multiple sclerosis management,it is selected from one of the following compounds: bencyclane,methylprednisolone, mitoxantrone, and prednisolone.

Typically, where the drug is a muscle relaxant, it is selected from oneof the following compounds: baclofen, chlorzoxazone, cyclobenzaprine,methocarbamol, orphenadrine, quinine, and tizanidine.

Typically, where the drug is a nonsteroidal anti-inflammatory, it isselected from one of the following compounds: aceclofenac,acetaminophen, alminoprofen, amfenac, aminopropylon, amixetrine,aspirin, benoxaprofen, bromfenac, bufexamac, carprofen, celecoxib,choline, salicylate, cinchophen, cinmetacin, clopriac, clometacin,diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen,indomethacin, indoprofen, ketoprofen, ketorolac, mazipredone,meclofenamate, nabumetone, naproxen, parecoxib, piroxicam, pirprofen,rofecoxib, sulindac, tolfenamate, tolmetin, and valdecoxib.

Typically, where the drug is an opioid, it is selected from one of thefollowing compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

Typically, where the drug is another analgesic it is selected from oneof the following compounds: apazone, benzpiperylon, benzydramine,caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine,propacetamol, and propoxyphene.

Typically, where the drug is an opthalmic preparation, it is selectedfrom one of the following compounds: ketotifen and betaxolol.

Typically, where the drug is an osteoporosis preparation, it is selectedfrom one of the following compounds: alendronate, estradiol,estropitate, risedronate and raloxifene.

Typically, where the drug is a prostaglandin, it is selected from one ofthe following compounds: epoprostanol, dinoprostone, misoprostol, andalprostadil.

Typically, where the drug is a respiratory agent, it is selected fromone of the following compounds: albuterol, ephedrine, epinephrine,fomoterol, metaproterenol, terbutaline, budesonide, ciclesonide,dexamethasone, flunisolide, fluticasone propionate, triamcinoloneacetonide, ipratropium bromide, pseudoephedrine, theophylline,montelukast, zafirlukast, ambrisentan, bosentan, enrasentan,sitaxsentan, tezosentan, iloprost, treprostinil, and pirfenidone

Typically, where the drug is a sedative and hypnotic, it is selectedfrom one of the following compounds: butalbital, chlordiazepoxide,diazepam, estazolam, flunitrazepam, flurazepam, lorazepam, midazolam,temazepam, triazolam, zaleplon, zolpidem, and zopiclone.

Typically, where the drug is a skin and mucous membrane agent, it isselected from one of the following compounds: isotretinoin, bergaptenand methoxsalen.

Typically, where the drug is a smoking cessation aid, it is selectedfrom one of the following compounds: nicotine and varenicline.

Typically, where the drug is a Tourette's syndrome agent, it ispimozide.

Typically, where the drug is a urinary tract agent, it is selected fromone of the following compounds: tolteridine, darifenicin, propanthelinebromide, and oxybutynin.

Typically, where the drug is a vertigo agent, it is selected from one ofthe following compounds: betahistine and meclizine.

In general, we have found that suitable drug have properties that makethem acceptable candidates for use with the devices and methods hereindescribed. For example, the drug compound is typically one that is, orcan be made to be, vaporizable. Typically, the drug is a heat stabledrug. Exemplary drugs include acebutolol, acetaminophen, alprazolam,amantadine, amitriptyline, apomorphine diacetate, apomorphinehydrochloride, atropine, azatadine, betahistine, brompheniramine,bumetanide, buprenorphine, bupropion hydrochloride, butalbital,butorphanol, carbinoxamine maleate, celecoxib, chlordiazepoxide,chlorpheniramine, chlorzoxazone, ciclesonide, citalopram, clomipramine,clonazepam, clozapine, codeine, cyclobenzaprine, cyproheptadine,dapsone, diazepam, diclofenac ethyl ester, diflunisal, disopyramide,doxepin, estradiol, ephedrine, estazolam, ethacrynic acid, fenfluramine,fenoprofen, flecainide, flunitrazepam, galanthamine, granisetron,haloperidol, hydromorphone, hydroxychloroquine, ibuprofen, imipramine,indomethacin ethyl ester, indomethacin methyl ester, isocarboxazid,ketamine, ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester,ketorolac ethyl ester, ketorolac methyl ester, ketotifen, lamotrigine,lidocaine, loperamide, loratadine, loxapine, maprotiline, memantine,meperidine, metaproterenol, methoxsalen, metoprolol, mexiletine HCl,midazolam, mirtazapine, morphine, nalbuphine, naloxone, naproxen,naratriptan, nortriptyline, olanzapine, orphenadrine, oxycodone,paroxetine, pergolide, phenytoin, pindolol, piribedil, pramipexole,procainamide, prochloperazine, propafenone, propranolol, pyrilamine,quetiapine, quinidine, rizatriptan, ropinirole, sertraline, selegiline,sildenafil, spironolactone, tacrine, tadalafil, terbutaline,testosterone, thalidomide, theophylline, tocainide, toremifene,trazodone, triazolam, trifluoperazine, valproic acid, venlafaxine,vitamin E, zaleplon, zotepine, amoxapine, atenolol, benztropine,caffeine, doxylamine, estradiol 17-acetate, flurazepam, flurbiprofen,hydroxyzine, ibutilide, indomethacin norcholine ester, ketorolacnorcholine ester, melatonin, metoclopramide, nabumetone, perphenazine,protriptyline HCl, quinine, triamterene, trimipramine, zonisamide,bergapten, chlorpromazine, colchicine, diltiazem, donepezil, eletriptan,estradiol-3,17-diacetate, efavirenz, esmolol, fentanyl, flunisolide,fluoxetine, hyoscyamine, indomethacin, isotretinoin, linezolid,meclizine, paracoxib, pioglitazone, rofecoxib, sumatriptan, tolterodine,tramadol, tranylcypromine, trimipramine maleate, valdecoxib, vardenafil,verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone,cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam,albuterol, apomorphine hydrochloride diacetate, carbinoxamine,clonidine, diphenhydramine, thambutol, fluticasone proprionate,fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone,oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamicacid, aripiprazole, astemizole, benazepril, clemastine, estradiol17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan,pyrilamine maleate, scopolamine, and triamcinolone acetonide andpharmaceutically acceptable analogs and equivalents thereof.

The drug may be one that when vaporized from a film on an impermeablesurface of a heat conductive substrate, the aerosol exhibits anincreasing level of drug composition degradation products withincreasing film thickness. Examples include but are not limited to thefollowing drugs, and associated ranges of film thicknesses:

-   -   alprazolam, film thickness between 0.1 and 10 μm;    -   amoxapine, film thickness between 2 and 20 μm;    -   atropine, film thickness between 0.1 and 10 μm;    -   bumetanide film thickness between 0.1 and 5 μm;    -   buprenorphine, film thickness between 0.05 and 10 μm;    -   butorphanol, film thickness between 0.1 and 10 μm;    -   clomipramine, film thickness between 1 and 8 μm;    -   donepezil, film thickness between 1 and 10 μm;    -   hydromorphone, film thickness between 0.05 and 10 μm;    -   loxapine, film thickness between 1 and 20 μm;    -   midazolam, film thickness between 0.05 and 20 μm;    -   morphine, film thickness between 0.2 and 10 μm;    -   nalbuphine, film thickness between 0.2 and 5 μm;    -   naratriptan, film thickness between 0.2 and 5 μm;    -   olanzapine, film thickness between 1 and 20 μm;    -   paroxetine, film thickness between 1 and 20 μm;    -   prochlorperazine, film thickness between 0.1 and 20 μm;    -   pramipexole, film thickness between 0.05 and 10 μm;    -   quetiapine, film thickness between 1 and 20 μm;    -   rizatriptan, film thickness between 0.2 and 20 μm;    -   sertraline, film thickness between 1 and 20 μm;    -   sibutramine, film thickness between 0.5 and 2 μm;    -   sildenafil, film thickness between 0.2 and 3 μm;    -   sumatriptan, film thickness between 0.2 and 6 μm;    -   tadalafil, film thickness between 0.2 and 5 μm;    -   vardenafil, film thickness between 0.1 and 2 μm;    -   venlafaxine, film thickness between 2 and 20 μm;    -   zolpidem, film thickness between 0.1 and 10 μm;    -   apomorphine HCl, film thickness between 0.1 and 5 μm;    -   celecoxib, film thickness between 2 and 20 μm;    -   ciclesonide, film thickness between 0.05 and 5 μm;    -   eletriptan, film thickness between 0.2 and 20 μm;    -   parecoxib, film thickness between 0.5 and 2 μm;    -   valdecoxib, film thickness between 0.5 and 10 μm;    -   fentanyl, film thickness between 0.05 and 5 μm;    -   citalopram, film thickness between 1 and 20 μm;    -   escitalopram, film thickness between 0.2 and 20 μm;    -   clonazepam, film thickness between 0.05 and 8 μm;    -   oxymorphone, film thickness between 0.1 and 10 μm;    -   albuterol, film thickness between 0.2 and 2 μm;    -   sufentanyl, film thickness between 0.05 and 5 μm; and    -   remifentanyl, film thickness between 0.05 and 5 μm.

Typically, the drugs of use in the invention have a molecular weight inthe range of about 150-700, preferably in the range of about 200-700,more preferably in the range of 250-600, still more preferably in therange of about 250-500. In some variations, the drugs have a molecularweight in the range 350-600 and in others the drugs have a molecularweigh in the range of about 300-450. In other variations, where the drugis a heat stable drug, the drug can have a molecular weight of 350 orgreater.

Typically, the compound is in its ester, free acid, or its free-baseform. However, it is not without possibility that the compound will bevaporizable from its salt form. Indeed, a variety of pharmaceuticallyacceptable salts are suitable for aerosolization. Illustrative saltsinclude, without limitation, the following: hydrochloric acid,hydrobromic acid, acetic acid, maleic acid, formic acid, and fumaricacid salts. Salt forms can be purchased commercially, or can be obtainedfrom their corresponding free acid or free base forms using well knownmethods in the art.

Suitable pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with the drug. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within these classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

Additionally, pharmaceutically acceptable carriers, surfactants,enhancers, and inorganic compounds may be included in the composition.Examples of such materials are known in the art.

In some variations, the aerosols are substantially free of organicsolvents and propellants. Additionally, water is typically not added asa solvent for the drug, although water from the atmosphere may beincorporated in the aerosol during formation, in particular, whilepassing air over the film and during the cooling process. In othervariations, the aerosols are completely devoid of organic solvents andpropellants. In yet other variations, the aerosols are completely devoidof organic solvents, propellants, and any excipients. These aerosolscomprise only pure drug, less than 10% drug degradation products, and acarrier gas, which is typically air.

Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05. Mostpreferably, the drug has a decomposition index less than 0.025

In some variations, the condensation aerosol comprises at least 5% byweight of condensation drug aerosol particles. In other variations, theaerosol comprises at least 10%, 20%, 30%, 40%, 50%, 60%, or 75% byweight of condensation drug aerosol particles. In still othervariations, the aerosol comprises at least 95%, 99%, or 99.5% by weightof condensation aerosol particles.

In some variations, the condensation aerosol particles comprise lessthan 10% by weight of a thermal degradation product. In othervariations, the condensation drug aerosol particles comprise less than5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a thermal degradation product.

In certain embodiments of the invention, the drug aerosol has a purityof between 90% and 99.8%, or between 93% and 99.7%, or between 95% and99.5%, or between 96.5% and 99.2%.

Typically, the aerosol has a number concentration greater than 10⁶particles/mL. In other variations, the aerosol has a numberconcentration greater than 10⁷ particles/mL. In yet other variations,the aerosol has a number concentration greater than 10⁸ particles/mL,greater than 10⁹ particles/mL, greater than 10¹⁰ particles/mL, orgreater than 10¹¹ particles/mL.

The gas of the aerosol typically is air. Other gases, however, can beused, in particular inert gases, such as argon, nitrogen, helium, andthe like. The gas can also include vapor of the composition that has notyet condensed to form particles. Typically, the gas does not includepropellants or vaporized organic solvents. In some variations, thecondensation aerosol comprises at least 5% by weight of condensationdrug aerosol particles. In other variations, the aerosol comprises atleast 10%, 20%, 30%, 40%, 50%, 60%, or 75% by weight of condensationdrug aerosol particles. In still other variations, the aerosol comprisesat least 95%, 99%, or 99.5% by weight of condensation aerosol particles.

In some variations the condensation drug aerosol has a MMAD in the rangeof about 1-3 μm. In some variations the geometric standard deviationaround the MMAD of the condensation drug aerosol particles is less than3.0. In other variations, the geometric standard deviation around theMMAD of the condensation drug aerosol particles is less than 2.5, orless than 2.0.

In certain embodiments of the invention, the drug aerosol comprises oneor more drugs having a 4TSR of at least 5 or 10, a 1.5TSR of at least 7or 14, or a 0.5TSR of at least 9 or 18. In other embodiments of theinvention, the drug aerosol comprises one or more drugs having a 4TSR ofbetween 5 and 100 or between 10 and 50, a 1.5TSR of between 7 and 200 orbetween 14 and 100, or a 0.5TSR of between 9 and 900 or between 18 and300.

Formation of Condensation Aerosols

Any suitable method may be used to form the condensation aerosolsdescribed herein. One such method involves the heating of a compositionto form a vapor, followed by cooling of the vapor so that it forms anaerosol (i.e., a condensation aerosol).

Typically, the composition is coated on a substrate, and then thesubstrate is heated to vaporize the composition. The substrate may be ofany geometry and be of a variety of different sizes. It is oftendesirable that the substrate provide a large surface to volume ratio(e.g., greater than 100 per meter) and a large surface to mass ratio(e.g., greater than 1 cm² per gram). The substrate can have more thanone surface

A substrate of one shape can also be transformed into another shape withdifferent properties. For example, a flat sheet of 0.25 mm thickness hasa surface to volume ratio of approximately 8,000 per meter. Rolling thesheet into a hollow cylinder of 1 cm diameter produces a support thatretains the high surface to mass ratio of the original sheet but has alower surface to volume ratio (about 400 per meter).

A number of different materials may be used to construct the substrate.Typically, the substrates are heat-conductive and include metals, suchas aluminum, iron, copper, stainless steel, and the like, alloys,ceramics, and filled polymers. In one variation, the substrate isstainless steel. Combinations of materials and coated variants ofmaterials may be used as well.

When it is desirable to use aluminum as a substrate, aluminum foil is asuitable material. Examples of alumina and silicon based materialsBCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry.

Typically it is desirable that the substrate have relatively few, orsubstantially no, surface irregularities. Although a variety of supportsmay be used, supports that have an impermeable surface, or animpermeable surface coating, are typically desirable. Illustrativeexamples of such supports include metal foils, smooth metal surfaces,nonporous ceramics, and the like. Alternatively, or in addition, topreferred substrates having an impermeable surface, the substratesurface expanse is characterized by a contiguous surface area of greaterthan 1 mm², preferably 10 mm², more preferable 50 mm² and still morepreferably 100 mm², and a material density of greater than 0.5 g/cc. Incontrast, non-preferred substrates typically have a substrate density ofless than 0.5 g/cc, such as, for example, yarn, felts and foam, or havea surface area of less than 1 mm²/particle such as, for example smallalumina particles, and other inorganic particles, as it is difficult onthese types of surfaces to generate therapeutic quantities of a drugaerosol with less than 10% drug degradation via vaporization.

In one variation of the invention, a stainless steel foil substrate wasemployed. For example, stainless steel was employed for drugs testedaccording to Method B and was resistively heated by placing thesubstrate between a pair of electrodes connected to a capacitor. FIG. 4Ais a plot of substrate temperature increase, measured in still air witha thin thermocouple (Omega, Model CO2-K), as a function of time, inseconds, for a stainless steel foil substrate resistively heated bycharging the capacitor to 13.5 V (lower line), 15 V (middle line), and16 V (upper line). When charged with 13.5 V, the substrate temperatureincrease was about 250° C. within about 200-300 milliseconds. As thecapacitor voltage increased, the peak temperature of the substrate alsoincreased. Charging the capacitor to 16V heated the foil substratetemperature about 375° C. in 200-300 milliseconds (to a maximumtemperature of about 400° C.).

FIG. 4B shows the time-temperature relationship for a stainless steelfoil substrate having a thickness of 0.005 inches. The foil substratewas heated by charging a capacitor, connected to the substrate throughelectrodes, to 16 V. The substrate reached its peak temperature of 400°C. in about 200 milliseconds, and maintained that temperature for the 1second testing period.

In Methods D and E, a hollow, stainless steel tube is used as thedrug-film substrate. The cylindrical tube in Method D had a diameter of13 mm and a length of 34 mm. The cylindrical tube in Method E had adiameter of 7.6 mm and a length of 51 mm. In Method D, the substrate wasconnected to two 1 Farad capacitors wired in parallel, whereas in MethodE, the substrate was connected to two capacitors (a 1 Farad and a 0.5Farad) wired in parallel. FIGS. 5A-5B show substrate temperature as afunction of time, for the cylindrical substrate of Method D. FIG. 5Bshows a detail of the first 1 second of heating.

In other variations, aluminum foil is used as a substrate for testingdrug, for example, as described in Methods C, F, and G.

The composition is typically coated on the solid support in the form ofa film. The film may be coated on the solid support using any suitablemethod. The method suitable for coating is often dependent upon thephysical properties of the compound and the desired film thickness. Oneexemplary method of coating a composition on a solid support is bypreparing a solution of compound (alone or in combination with otherdesirable compounds) in a suitable solvent, applying the solution to theexterior surface of the solid support, and then removing the solvent(e.g., via evaporation, etc.) thereby leaving a film on the supportsurface.

Common solvents include methanol, dichloromethane, methyl ethyl ketone,diethyl ether, 3:1 chloroform:methanol mixture, 1:1 dichloromethane:methyl ethyl ketone mixture, dimethylformamide, and deionized water. Insome instances (e.g., when triamterene is used), it is desirable to usea solvent such as formic acid. Sonication may also be used as necessaryto dissolve the compound.

The composition may also be coated on the solid support by dipping thesupport into a composition solution, or by spraying, brushing orotherwise applying the solution to the support. Alternatively, a melt ofthe drug can be prepared and applied to the support. For drugs that areliquids at room temperature, thickening agents can be mixed with thedrug to permit application of a solid drug film.

The film can be of varying thickness depending on the compound and themaximum amount of thermal degradation desired. In one method, theheating of the composition involves heating a thin film of thecomposition having a thickness between about 0.05 μm-20 μm to form avapor. In yet other variations, the composition has a film thicknessbetween about 0.5 μm-10 μm. Most typically, the film thickness vaporizedis between 0.5 μm-5 μm.

The support on which the film of the composition is coated can be heatedby a variety of means to vaporize the composition. Exemplary methods ofheating include the passage of current through an electrical resistanceelement, absorption of electromagnetic radiation (e.g., microwave orlaser light) and exothermic chemical reactions (e.g., exothermicsolvation, hydration of pyrophoric materials, and oxidation ofcombustible materials). Heating of the substrate by conductive heatingis also suitable. One exemplary heating source is described in U.S.patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, U.S. Ser. No. 60/472,697 filed May 21, 2003. Thedescription of the exemplary heating source disclosed therein, is herebyincorporated by reference.

Heat sources typically supply heat to the substrate at a rate thatachieves a substrate temperature of at least 200° C., preferably atleast 250° C., or more preferably at least 300° C. or 350° C., andproduces substantially complete volatilization of the drug compositionfrom the substrate within a period of 2 seconds, preferably, within 1second, or more preferably within 0.5 seconds. Suitable heat sourcesinclude resistive heating devices which are supplied current at a ratesufficient to achieve rapid heating, e.g., to a substrate temperature ofat least 200° C., 250° C., 300° C., or 350° C. preferably within 50-500ms, more preferably in the range of 50-200 ms. Heat sources or devicesthat contain a chemically reactive material which undergoes anexothermic reaction upon actuation, e.g., by a spark or heat element,such as flashbulb type heaters of the type described in severalexamples, and the heating source described in the above-cited U.S.patent application for SELF-CONTAINED HEATING UNIT AND DRUG-SUPPLY UNITEMPLOYING SAME, are also suitable. In particular, heat sources thatgenerate heat by exothermic reaction, where the chemical “load” of thesource is consumed in a period of between 50-500 msec or less aregenerally suitable, assuming good thermal coupling between the heatsource and substrate.

When heating the thin film of the composition, to avoid decomposition,it is desirable that the vaporized compound should transition rapidlyfrom the heated surface or surrounding heated gas to a coolerenvironment. This may be accomplished not only by the rapid heating ofthe substrate, but also by the use of a flow of gas across the surfaceof the substrate. While a vaporized compound from a surface maytransition through Brownian motion or diffusion, the temporal durationof this transition may be impacted by the extent of the region ofelevated temperature at the surface, which is established by thevelocity gradient of gases over the surface and the physical shape ofsurface. Thus decomposition can be controlled by providing a flow of gasto create a high velocity gradient (a rapid increase in velocitygradient near the surface), which results in minimization of the hot gasregion above the heated surface and decreases the time of transition ofthe vaporized compound to a cooler environment, and/or by use of asmoother substrate surface to facilitate the transition of the hot gasesfrom the heated surface, by precluding entrapment of the hot gases andcompound vapor in, for example, depressions, pockets or pores on thesurface. Typical gas-flow rates used to minimize such decomposition andto generate a desired particle size are in the range of 4-50 L/minute

The aerosol particles for administration can typically be formed usingany of the describe methods at a rate of greater than 10⁸ inhalableparticles per second. In some variations, the aerosol particles foradministration are formed at a rate of greater than 10⁹ or 10¹⁰inhalable particles per second. Similarly, with respect to aerosolformation (i.e., the mass of aerosolized particulate matter produced bya delivery device per unit time) the aerosol may be formed at a rategreater than 0.25 mg/second, greater than 0.5 mg/second, or greater than1 or 2 mg/second. Further, with respect to aerosol formation, focusingon the drug aerosol formation rate (i.e., the rate of drug compoundreleased in aerosol form by a delivery device per unit time), the drugmay be aerosolized at a rate greater than 0.5 mg drug per second,greater than 0.1 mg drug per second, greater than 0.5 mg drug persecond, or greater than 1 or 2 mg drug per second.

In some variations, the drug condensation aerosols are formed fromcompositions that provide at least 5% by weight of drug condensationaerosol particles. In other variations, the aerosols are formed fromcompositions that provide at least 10%, 20%, 30%, 40%, 50%, 60%, or 75%by weight of drug condensation aerosol particles. In still othervariations, the aerosols are formed from compositions that provide atleast 95%, 99%, or 99.5% by weight of drug condensation aerosolparticles.

In some variations, the drug condensation aerosol particles when formedcomprise less than 10% by weight of a thermal degradation product. Inother variations, the drug condensation aerosol particles when formedcomprise less than 5%, 1%, 0.5%, 0.1%, or 0.03% by weight of a thermaldegradation product.

In some variations the drug condensation aerosols are produced in a gasstream at a rate such that the resultant aerosols have a MMAD in therange of about 1-3 μm. In some variations the geometric standarddeviation around the MMAD of the drug condensation aerosol particles isless than 3.0. In other variations, the geometric standard deviationaround the MMAD of the drug condensation aerosol particles is less than2.5, or less than 2.0.

Delivery Devices

The delivery devices described herein for administering a condensationdrug aerosol typically comprise an element for heating the compositionto form a vapor and an element allowing the vapor to cool, therebyforming a condensation aerosol. These aerosols are generally deliveredvia inhalation to lungs of a patient, for local or systemic treatment.Alternatively, however, the condensation aerosols of the invention canbe produced in an air stream, for application of drug-aerosol particlesto a target site. For example, a stream of air carrying drug-aerosolparticles can be applied to treat an acute or chronic skin condition,can be applied during surgery at the incision site, or can be applied toan open wound. The delivery device may be combined with a compositioncomprising a drug in unit dose form for use as a kit.

One suitable device for inhalation is illustrated in FIG. 27. Deliverydevice 100 has a proximal end 102 and a distal end 104, a solid support106, a power source 108, and a mouthpiece 110. In this depiction, solidsupport 106 also comprises a heating module. A composition is depositedon solid support 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element, etc.).

The composition vaporizes and condenses to form a condensation aerosolprior to reaching the mouthpiece 110 at the proximal end of the device102. Air flow traveling from the device distal end 104 to the mouthpiece110 carries the condensation aerosol to the mouthpiece 110, where it isinhaled by a user.

The devices described herein may additionally contain a variety ofcomponents to facilitate aerosol delivery. For instance, the device mayinclude any component known in the art to control the timing of drugaerosolization relative to inhalation (e.g., breath-actuation).Similarly, the device may include a component to provide feedback topatients on the rate and/or volume of inhalation, or a component toprevent excessive use (i.e., “lockout” feature). In addition, the devicemay further include a component to prevent use by unauthorizedindividuals, and a component to record dosing histories. Thesecomponents may be used alone, or in combination with other components.

The element that allows cooling may be of any configuration. Forexample, it may be an inert passageway linking the heating means to theinhalation means. Similarly, the element permitting inhalation by a usermay be of any configuration. For example, it may be an exit portal thatforms a connection between the cooling element and the user'srespiratory system.

Other suitable devices for use with the aerosols described herein areshown in FIGS. 2A and 2B. As shown in FIG. 2A, there is a device 30comprising an element for heating a composition to form a vapor, anelement allowing the vapor to cool, thereby forming a condensationaerosol, and an element permitting a user to inhale the aerosol. Device30 also comprises a housing 32 with a tapered end 34 for insertion intothe mouth of a user. On the end opposite tapered end 34, the housing hasone or more openings, such as slots 36, for air intake when a userplaces the device in the mouth and inhales a breath. Within housing 32is a drug supply article 38, visible in the cut-away portion of thefigure. Drug supply article 38 includes a substrate 40 coated on itsexternal surface with a film 42 of a therapeutic drug to be delivered tothe user.

Typically, the drug supply article 38 is heated to a temperaturesufficient to vaporize all or a portion of the film 42, so that thecomposition forms a vapor that becomes entrained in a stream of airduring inhalation. As noted above, heating of the drug supply article 38may be accomplished using, for example, an electrically-resistive wireembedded or inserted into the substrate and connected to a batterydisposed in the housing. The heating can be actuated, for example, witha button on the housing or via breath actuation, as is known in the art.

FIG. 2B shows another device that may be used to form and deliver theaerosols described herein. The device, 50 comprises an element forheating a composition to form a vapor, an element allowing the vapor tocool, thereby forming a condensation aerosol, and an element permittinga user to inhale the aerosol. The device also comprises an upperexternal housing member 52 and a lower external housing member 54 thatfit together.

Shown in the depiction of FIG. 2B, the downstream end of each housingmember is gently tapered for insertion into a user's mouth, as best seenon upper housing member 52 at downstream end 56. The upstream end of theupper and lower housing members are slotted, as seen best in the figurein the upper housing member at 58, to provide for air intake when a userinhales. The upper and lower housing members when fitted together definea chamber 60. Positioned within chamber 60 is a drug supply unit 62,shown in a partial cut-away view.

As shown in FIG. 2B, the drug supply unit has a tapered substantiallycylindrical substrate 64. However, as described above the solid supportmay be of any desirable configuration. At least a portion of the surface68 of the substrate 64 is coated with a composition film 66. Visible inthe cut-away portion of the drug-supply unit is an interior region 70 ofthe substrate containing a substance suitable to generate heat. Thesubstance can be a solid chemical fuel, chemical reagents that mixexothermically, electrically resistive wire, etc. A power supply source,if needed for heating, and any necessary valving for the inhalationdevice may be contained in end piece 72. In one variation of the devicesused, the device includes a drug composition delivery article composedof the substrate, a film of the selected drug composition on thesubstrate surface, and a heat source for supplying heat to the substrateat a rate effective to heat the substrate to a temperature greater than200° C. or in other embodiments to a temperature greater than 250° C.,300° C. or 350° C., and to produce substantially complete volatilizationof the drug composition within a period of 2 seconds or less.

FIGS. 1A and 1B provide exploded views of other drug supply articlesthat may be used in combination with the devices described herein. Asshown in FIG. 1A, there is a drug supply article comprising a heatconducting substrate 10 having a composition coating 18 at least aportion of the upper surface 14. While the coating 18 is shown on uppersurface 14 in FIG. 1A, it should be understood that it need not be so.Indeed, the coating may be placed on any suitable surface, such assurfaces 16 and 12. Various methods of coatings are known in the artand/or have been described above.

FIG. 1B provides a perspective, cut-away view of another drug supplyarticle 20 that may be used with the methods and devices hereindescribed. As shown there, the article 20 comprises a cylinder-shapedsubstrate 22. This substrate may be formed from a heat-conductivematerial, for example. The exterior surface 24 of substrate 22 is coatedwith a composition 26. As shown in the cut-away portion, there is aheating element 28 disposed in the substrate. The substrate can behollow with a heating element inserted into the hollow space or solidwith a heating element incorporated into the substrate.

The illustrative heating element shown in FIG. 1B is shown as anelectrical resistive wire that produces heat when a current flowsthrough it, but as noted above, a number of different heating methodsand corresponding devices are acceptable. For example, acceptable heatsources can supply heat to the drug supply article at rates that rapidlyachieve a temperature sufficient to completely vaporize the compositionfrom the support surface. For example, heat sources that achieve atemperature of 200° C. to 500° C. or more within a period of 2 secondsare typical, although it should be appreciated that the temperaturechosen will be dependent upon the vaporization properties of thecomposition, but is typically heated to a temperature of at least about200° C., preferably of at least about 250° C., more preferably at leastabout 300° C. or 350° C. Heating the substrate produces a drugcomposition vapor that in the presence of the flowing gas generatesaerosol particles in the desired size range. The presence of the gasflow is generally prior to, simultaneous with, or subsequent to heatingthe substrate. In one embodiment, the substrate is heated for a periodof less than about 1 second, and more preferably for less than about 500milliseconds, still more preferably for less than about 200milliseconds. The drug-aerosol particles are inhaled by a subject fordelivery to the lung.

FIGS. 3A-3E are high speed photographs showing the generation of aerosolparticles from a drug-supply unit. FIG. 3A shows a heat-conductivesubstrate about 2 cm in length coated with a film of drug. Thedrug-coated substrate was placed in a chamber through which a stream ofair was flowing in an upstream-to-downstream direction (from left toright in FIG. 3) at rate of about 15 L/min. The substrate waselectrically heated and the progression of drug vaporization monitoredby real-time photography. FIGS. 3B-3E show the sequence of drugvaporization and aerosol generation at time intervals of 50 milliseconds(msec), 100 msec, 200 msec, and 500 msec, respectively. The white cloudof drug-aerosol particles formed from the drug vapor entrained in theflowing air is visible in the photographs. Complete vaporization of thedrug film was achieved by 500 msec.

The device may also include a gas-flow control valve disposed upstreamof the solid support, for limiting gas-flow rate through thecondensation region. The gas-flow valve may, for example, include aninlet port communicating with the chamber, and a deformable flap adaptedto divert or restrict airflow away from the port increasingly, withincreasing pressure drop across the valve. Similarly, the gas-flow valvemay include an actuation switch. In this variation, the valve movementwould be in response to an air pressure differential across the valve,which for example, could function to close the switch. The gas-flowvalve may also include an orifice designed to limit airflow rate intothe chamber.

The device may also include a bypass valve communicating with thechamber downstream of the unit for offsetting the decrease in airflowproduced by the gas-flow control valve, as the user draws air into thechamber. In this way, the bypass valve could cooperate with thegas-control valve to control the flow through the condensation region ofthe chamber as well as the total amount of air being drawn through thedevice. Thus the total volumetric airflow through the device in thisvariation would be the sum of the volumetric airflow rate through thegas-control valve and the volumetric airflow rate through the bypassvalve.

The gas control valve could, for example, function to limit air drawninto the device to a preselected level, e.g., 15 L/minute. In this way,airflow for producing particles of a desired size may be preselected andproduced. For example, once this selected airflow level is reached,additional air drawn into the device would create a pressure drop acrossthe bypass valve, which in turn would accommodate airflow through thebypass valve into the downstream end of the device adjacent the user'smouth. Thus, the user senses a full breath being drawn in, with the twovalves distributing the total airflow between desired airflow rate andbypass airflow rate.

These valves may be used to control the gas velocity through thecondensation region of the chamber and hence to control the particlesize of the aerosol particles produced. Typically, the faster theairflow, the smaller the particles are. Thus, to achieve smaller orlarger particles, the gas velocity through the condensation region ofthe chamber may be altered by modifying the gas-flow control valve toincrease or decrease the volumetric airflow rate. For example, toproduce condensation particles in the size range of about 1-3.5 μm MMAD,a chamber having substantially smooth-surfaced walls would have aselected gas-flow rate in the range of 4-50 L/minute.

Additionally, as will be appreciated by one of skill in the art,particle size may be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate, and/or the presence or absence ofstructures that produce turbulence within the chamber. Thus, for exampleto produce condensation particles in the size range 10-100 nm MMAD, thechamber may provide gas-flow barriers for creating air turbulence withinthe condensation chamber. These barriers are typically placed within afew thousandths of an inch from the substrate surface. Particle size isdiscussed in more detail below. Additionally, the drug supply unitsdisclosed herein can also be used to generate a drug vapor that canreadily be mixed with gas to produce an aerosol for topical delivery,typically by a spray nozzle, to a topical site for a variety oftreatment regimens, including acute or chronic treatment of a skincondition, administration of a drug to an incision site during surgeryor to an open wound. Rapid vaporization of the drug film occurs withminimal thermal decomposition of the drug.

Drug Composition Film Thickness

Typically, the drug composition film coated on the solid support has athickness of between about 0.05-20 μm, and typically a thickness between0.1-15 μm. More typically, the thickness is between about 0.2-10 μm;even more typically, the thickness is between about 0.5-10 μm, and mosttypically, the thickness is between about 0.5-5 μm. The desirable filmthickness for any given drug composition is typically determined by aniterative process in which the desired yield and purity of thecondensation aerosol composition are selected or known.

For example, if the purity of the particles is less than that which isdesired, or if the percent yield is less than that which is desired, thethickness of the drug film is adjusted to a thickness different from theinitial film thickness. The purity and yield are then determined at theadjusted film thickness, and this process is repeated until the desiredpurity and yield are achieved. After selection of an appropriate filmthickness, the area of substrate required to provide a therapeuticallyeffective dose is determined. Generally, the film thickness for a givendrug composition is such that drug-aerosol particles, formed byvaporizing the drug composition by heating the substrate and entrainingthe vapor in a gas stream, have (i) 10% by weight or lessdrug-degradation product, more preferably 5% by weight or less, mostpreferably 2.5% by weight or less and (ii) at least 50% of the totalamount of drug composition contained in the film. The area of thesubstrate on which the drug composition film is formed is selected toachieve an effective human therapeutic dose of the drug aerosol as isdescribed further below. Examples of how film thickness affects puritywere conducted in support of the invention and are described below. Avariety of drugs were deposited on a heat-conductive, impermeablesubstrate and the substrate was heated to a temperature sufficient togenerate a thermal vapor. Purity of drug-aerosol particles in thethermal vapor was determined by a suitable analytical method. Threedifferent substrate materials were used in the studies: stainless steelfoil, aluminum foil, and a stainless steel cylinder. Methods B-G belowdetail the procedures for forming a drug film on each substrate and themethod of heating each substrate.

In Examples 1-236 below, a substrate containing a drug film of a certainthickness was prepared. To determine the thickness of the drug film, onemethod that can be used is to determine the area of the substrate andcalculate drug film thickness using the following relationship:

film thickness(cm)=drug mass(g)/[drug density(g/cm³)×substratearea(cm²)]

The drug mass can be determined by weighing the substrate before andafter formation of the drug film or by extracting the drug and measuringthe amount analytically. Drug density can be experimentally determinedby a variety of techniques, known by those of skill in the art or foundin the literature or in reference texts, such as in the CRC. Anassumption of unit density is acceptable if an actual drug density isnot known.

In the studies reported in the Examples, the substrate having a drugfilm of known thickness was heated to a temperature sufficient togenerate a thermal vapor. All or a portion of the thermal vapor wasrecovered and analyzed for presence of drug-degradation products, todetermine purity of the aerosol particles in the thermal vapor. Severaldrugs are discussed here as merely exemplary of the studies reported inExamples 1-236. Example 10 describes preparation of a drug-supplyarticle containing atropine, a muscarinic antagonist. Substratescontaining films of atropine ranging in thickness from between about 1.7μm to about 9.0 μm were prepared. The stainless steel substrates wereheated and the purity of the drug-aerosol particles in the thermal vaporgenerated from each substrate was determined. FIG. 6 shows the results,where drug aerosol purity as a function of drug film thickness isplotted. There is a clear relationship between film thickness andaerosol particle purity, where as the film thickness decreases, thepurity increases. An atropine film having a thickness of 9.0 μm produceda thermal vapor having a purity of 91%; an atropine film having athickness of 1.7 μm produced a thermal vapor having a purity of 98%.

Hydromorphone, an analgesic, was also tested, as described in Example66. Substrates having a drug film thickness of between about 0.7 μm toabout 2.7 μm were prepared and heated to generate a thermal vapor.Purity of the aerosol particles improved as the thickness of the drugfilm on the substrate decreased.

FIG. 7 shows the relationship between drug film thickness andaerosol-purity for donepezil. As described in Example 44, donepezil wascoated onto foil substrates to film thicknesses ranging from about 0.5μm to about 3.2 μm. Purity of the aerosol particles from each of thefilms on the substrates was analyzed. At drug film thicknesses of 1.5 μmto 3.2 μm, purity of the aerosol particles improved as thickness of thedrug film on the substrate decreased, similar to the trend found foratropine and hydromorphone. In contrast, at less than 1.5 μm thickness,purity of the aerosol particles worsened as thickness of the drug filmon the substrate decreased. A similar pattern was also observed foralbuterol, as described in Example 3, with aerosol particles puritypeaking for films of approximately 1 μm, and decreasing for both thinnerand thicker films as shown in FIG. 23.

FIGS. 9-23 present data for aerosol purity as a function of filmthickness for the following compounds: buprenorphine (Example 16),clomipramine (Example 28), ciclesonide (Example 26), midazolam (Example100), nalbuphine (Example 103), naratriptan (Example 106), olanzapine(Example 109), quetiapine (Example 127), tadalafil (Example 140),prochlorperazine (Example 122), zolpidem (Example 163), fentanyl(Example 57), alprazolam (Example 4), sildenafil (Example 134), andalbuterol (Example 3).

In FIGS. 6-23, the general relationship between increasing aerosolpurity with decreasing film thickness is apparent; however the extent towhich aerosol purity varies with a change in film thickness varies foreach drug composition. For example, aerosol purity of sildenafil (FIG.22) exhibited a strong dependence on film thickness, where films about0.5 μm in thickness had a purity of greater than 99% and films of about1.6 μm in thickness had a purity of between 94-95%. In contrast, formidazolam (FIG. 12), increasing the film thickness from approximately1.2 μm to approximately 5.8 μm resulted in a decrease in aerosolparticle purity from greater than 99.9% to approximately 99.5%, asmaller change in particle purity despite a larger increase in filmthickness compared with the sildenafil example. Moreover, as wasdiscussed above, the inverse relationship between film thickness andpurity of aerosolized drug observed for many compounds in the thicknessrange less than about 20 μm does not necessarily apply at the thinnestfilm thicknesses that were tested. Some compounds, such as illustratedby donepezil (FIG. 7) show a rather pronounced decrease in purity atfilm thicknesses both below and above an optimal film thickness, in thiscase, above and below about 2 μm film thicknesses.

One way to express the dependence of aerosol purity on film thickness isby the slope of the line from a plot of aerosol purity against filmthickness. For compounds such as donepezil (FIG. 7), the slope of theline is taken from the maximum point in the curve towards the higherfilm thickness. Table 1, discussed below, shows the slope of the linefor the curves shown in FIGS. 6-23. Particularly preferred compounds fordelivery by the various embodiments of the present invention arecompounds with a substantial (i.e., highly negative) slope of the lineon the aerosol purity versus thickness plot, e.g., a slope more negativethan −0.1% purity per micron and more preferably −0.5% purity permicron.

In addition to selection of a drug film thickness that provides aerosolparticles containing 10% or less drug-degradation product (i.e., anaerosol particle purity of 90% or more), the film thickness is selectedsuch that at least about 50% of the total amount of drug compositioncontained in the film is vaporized when the substrate is heated to atemperature sufficient to vaporize the film. In the studies describedherein, the percentage of drug film vaporized was determined byquantifying (primarily by HPLC or weight) the mass of drug compositioncollected upon vaporization or alternatively by the amount of substratemass decrease. The mass of drug composition collected after vaporizationand condensation was compared with the starting mass of the drugcomposition film that was determined prior to vaporization to determinea percent yield, also referred to herein as a percent emitted. Thisvalue is indicated in many of the Examples set forth below. For example,in Example 1 a film having a thickness of 1.1 μm was formed from thedrug acebutolol, a beta-adrenergic blocking agent. The mass coated onthe substrate was 0.89 mg and the mass of drug collected in the thermalvapor was 0.53 mg, to give a 59.6 percent yield. After vaporization, thesubstrate and the testing chamber were washed to recover any remainingdrug. The total drug recovered from the test apparatus, including theemitted thermal vapor, was 0.81 mg, to give a 91% total recovery. Inanother example, midazolam was coated onto an impermeable substrate, asdescribed in Example 100. A drug film having a thickness of 9 μm wasformed. Heating of the substrate generated a thermal vapor containingdrug aerosol particles having a purity of 99.5%. The fraction of drugfilm collected on the filter, i.e., the percent yield, was 57.9%. Aftervaporization, the substrate and the testing chamber were washed torecover any remaining drug. The total drug recovered from the testapparatus and the filter was 5.06 mg, to give a 94.2% total recovery.

In the examples, the following drugs were vaporized and condensed togenerate condensation aerosol having a purity of 90% or greater:acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline,apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine,betahistine, brompheniramine, bumetanide, buprenorphine, bupropionhydrochloride, butalbital, butorphanol, carbinoxamine maleate,celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone,ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine,cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethylester, diflunisal, disopyramide, doxepin, estradiol, ephedrine,estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide,flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone,hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester,indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen,ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester,ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide,loratadine, loxapine, maprotiline, memantine, meperidine,metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam,mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan,nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine,pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide,prochloperazine, propafenone, propranolol, pyrilamine, quetiapine,quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil,spironolactone, tacrine, tadalafil, terbutaline, testosterone,thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam,trifluoperazine, valproic acid, venlafaxine, vitamin E, zaleplon,zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine,estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide,indomethacin norcholine ester, ketorolac norcholine ester, melatonin,metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine,triamterene, trimipramine, zonisamide, bergapten, chlorpromazine,colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate,efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine,indomethacin, isotretinoin, linezolid, meclizine, paracoxib,pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol,tranylcypromine, trimipramine maleate, valdecoxib, vardenafil,verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone,cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam,albuterol, apomorphine hydrochloride diacetate, carbinoxamine,clonidine, diphenhydramine, thambutol, fluticasone proprionate,fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone,oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamicacid, aripiprazole, astemizole, benazepril, clemastine, estradiol17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan,pyrilamine maleate, scopolamine, and triamcinolone acetonide.

Of these compounds, the following drugs were vaporized from thin filmsand formed condensation aerosols having greater than 95% purity:acebutolol, acetaminophen, alprazolam, amantadine, amitriptyline,apomorphine diacetate, apomorphine hydrochloride, atropine, azatadine,betahistine, brompheniramine, bumetanide, buprenorphine, bupropionhydrochloride, butalbital, butorphanol, carbinoxamine maleate,celecoxib, chlordiazepoxide, chlorpheniramine, chlorzoxazone,ciclesonide, citalopram, clomipramine, clonazepam, clozapine, codeine,cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethylester, diflunisal, disopyramide, doxepin, estradiol, ephedrine,estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide,flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone,hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester,indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen,ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester,ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide,loratadine, loxapine, maprotiline, memantine, meperidine,metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam,mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan,nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine,pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide,prochloperazine, propafenone, propranolol, pyrilamine, quetiapine,quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil,spironolactone, tacrine, tadalafil, terbutaline, testosterone,thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam,trifluoperazine, valproic acid, venlafaxine, vitamin E, zaleplon,zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine,estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide,indomethacin norcholine ester, ketorolac norcholine ester, melatonin,metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine,triamterene, trimipramine, zonisamide, bergapten, chlorpromazine,colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate,efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine,indomethacin, isotretinoin, linezolid, meclizine, paracoxib,pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol,tranylcypromine, trimipramine maleate, valdecoxib, vardenafil,verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone,cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, andtemazepam.

Drugs, exemplified in the Examples below, which formed condensationaerosols from a thin film having a purity of 98% or greater were thefollowing: acebutolol, acetaminophen, alprazolam, amantadine,amitriptyline, apomorphine diacetate, apomorphine hydrochloride,atropine, azatadine, betahistine, brompheniramine, bumetanide,buprenorphine, bupropion hydrochloride, butalbital, butorphanol,carbinoxamine maleate, celecoxib, chlordiazepoxide, chlorpheniramine,chlorzoxazone, ciclesonide, citalopram, clomipramine, clonazepam,clozapine, codeine, cyclobenzaprine, cyproheptadine, dapsone, diazepam,diclofenac ethyl ester, diflunisal, disopyramide, doxepin, estradiol,ephedrine, estazolam, ethacrynic acid, fenfluramine, fenoprofen,flecainide, flunitrazepam, galanthamine, granisetron, haloperidol,hydromorphone, hydroxychloroquine, ibuprofen, imipramine, indomethacinethyl ester, indomethacin methyl ester, isocarboxazid, ketamine,ketoprofen, ketoprofen ethyl ester, ketoprofen methyl ester, ketorolacethyl ester, ketorolac methyl ester, ketotifen, lamotrigine, lidocaine,loperamide, loratadine, loxapine, maprotiline, memantine, meperidine,metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam,mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan,nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine,pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide,prochloperazine, propafenone, propranolol, pyrilamine, quetiapine,quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil,spironolactone, tacrine, tadalafil, terbutaline, testosterone,thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam,trifluoperazine, valproic acid, venlafaxine, vitamin E, zaleplon,zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine,estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide,indomethacin norcholine ester, ketorolac norcholine ester, melatonin,metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine,triamterene, trimipramine, and zonisamide.

To obtain higher purity aerosols one can coat a lesser amount of drug,yielding a thinner film to heat, or alternatively use the same amount ofdrug but a larger surface area. Generally, except for, as discussedabove, extremely thin thickness of drug film, a linear decrease in filmthickness is associated with a linear decrease in impurities. Thus forthe drug composition where the aerosol exhibits an increasing level ofdrug degradation products with increasing film thicknesses, particularlyat a thickness of greater than 0.05-20 microns, the film thickness onthe substrate will typically be between 0.05 and 20 microns, e.g., themaximum or near-maximum thickness within this range that allowsformation of a particle aerosol with drug degradation less than 5%.Other drugs may show less than 5-10% degradation even at filmthicknesses greater than 20 microns. For these compounds, a filmthickness greater than 20 microns, e.g., 20-50 microns, may be selected,particularly where a relatively large drug dose is desired. In addition,to adjusting film thickness other modifications can be made to improvethe purity or yield of the aerosol generated. One such method involvesthe use of an altered form of the drug, such as, for example but notlimitation, use of a prodrug, or a free base, free acid or salt form ofthe drug. As demonstrated in various Examples below, modifying the formof the drug can impact the purity and or yield of the aerosol obtained.Although not always the case, the free base or free acid form of thedrug as opposed to the salt, generally results in either a higher purityor yield of the resultant aerosol. Thus, in a preferred embodiment ofthe invention, the free base and free acid forms of the drugs are used.

Another approach contemplates generation of drug-aerosol particleshaving a desired level of drug composition purity by forming the thermalvapor under a controlled atmosphere of an inert gas, such as argon,nitrogen, helium, and the like. Various Examples below show that achange in purity can be observed upon changing the gas under whichvaporization occurs.

Examples 166-233 correspond to studies conducted on drugs that whendeposited as a thin film on a substrate produced a thermal vapor havinga drug purity of less than about 90% but greater than about 60% or wherethe percent yield was less than about 50%. Purity of the thermal vaporof many of these drugs would be improved by using one or more of theapproaches discussed above.

Once a desired purity and yield have been achieved or can be estimatedfrom a graph of aerosol purity versus film thickness and thecorresponding film thickness determined, the area of substrate requiredto provide a therapeutically effective dose is determined.

Substrate Area

As noted above, the surface area of the substrate surface area isselected such that it is sufficient to yield a therapeutically effectivedose. The amount of drug to provide a therapeutic dose is generallyknown in the art and is discussed more below. The required dosage andselected film thickness, discussed above, dictate the minimum requiredsubstrate area in accord with the following relationship:

film thickness(cm)×drug density(g/cm³)×substrate area(cm²)=dose(g)

OR

Substrate area(cm²)=dose(g)/[film thickness(cm)×drug density(g/cm³)

The drug mass can be determined by weighing the substrate before andafter formation of the drug film or by extracting the drug and measuringthe amount analytically. Drug density can be determined experimentallyby a variety of well known techniques, or may be found in the literatureor in reference texts, such as in the CRC. An assumption of unit densityis acceptable if an actual drug density is not known.

To prepare a drug supply article comprised of a drug film on aheat-conductive substrate that is capable of administering an effectivehuman therapeutic dose, the minimum substrate surface area is determinedusing the relationships described above to determine a substrate areafor a selected film thickness that will yield a therapeutic dose of drugaerosol. Table 1 shows a calculated substrate surface area for a varietyof drugs on which an aerosol purity—film thickness profile wasconstructed.

TABLE 1 Slope of Line on Typical Calculated aerosol purity vs. DosePreferred Film Substrate Surface thickness plot (% Drug (mg) Thickness(μm) Area (cm²) purity/micron) Albuterol 0.2 0.1-10 0.2-20   −0.64 (FIG.23) Alprazolam 0.25 0.1-10 0.25-25   −0.44 (FIG. 21) Amoxapine 25   2-2012.5-125   Atropine 0.4 0.1-10 0.4-40   −0.93 (FIG. 6) Bumetanide 0.50.1-5  1-50 Buprenorphine 0.3 0.05-10  0.3-60   −0.63 (FIG. 9)Butorphanol 1 0.1-10  1-100 Clomipramine 50  1-8 62-500 −1.0 (FIG. 10)Donepezil 5   1-10 5-50 −0.38 (FIG. 7) Hydromorphone 2 0.05-10    2-400−0.55 (FIG. 8) Loxapine 10   1-20  5-100 Midazolam 1 0.05-20  0.5-200 −0.083 (FIG. 12) Morphine 5 0.2-10  5-250 Nalbuphine 5 0.2-5  10-250−1.12 (FIG. 13) Naratriptan 1 0.2-5  2-50 −1.42 (FIG. 14) Olanzapine 10  1-20  5-100 −0.16 (FIG. 15) Paroxetine 20   1-20 10-200Prochlorperazine 5 0.1-20 2.5-500  −0.11 (FIG. 18) Quetiapine 50   1-2025-500 −0.18 (FIG. 16) Rizatriptan 3 0.2-20 1.5-150  Sertraline 25  1-20 12.5-250   Sibutramine 10 0.5-2  50-200 Sildenafil 6 0.2-3 20-300 −3.76 (FIG. 22) Sumatriptan 3 0.2-6   5-150 Tadalafil 3 0.2-5  6-150 −1.52 (FIG. 17) Testosterone 3 0.2-20 1.5-150  Vardenafil 30.1-2  15-300 Venlafaxine 50   2-20 25-250 Zolpidem 5 0.1-10  5-500−0.88 (FIG. 19) Apomorphine 2 0.1-5   4-200 HCl Celecoxib 50   2-2025-250 Ciclesonide 0.2 0.05-5  0.4-40   −1.70 (FIG. 11) Fentanyl 0.050.05-5  0.1-10   Eletriptan 3 0.2-20 1.5-150  Parecoxib 10 0.5-2  50-200Valdecoxib 10 0.5-10 10-200

In some variations, the selected substrate surface area is between about0.05-500 cm². In others, the surface area is between about 0.05 and 300cm². Typically the surface area is between 0.5 and 250 cm².Particularly, preferred substrate surface areas, are between 0.5 and 100cm².

The actual dose of drug delivered, i.e., the percent yield or percentemitted, from the drug-supply article will depend on, along with otherfactors, the percent of drug film that is vaporized upon heating thesubstrate. Thus, for drug films that yield upon heating 100% of the drugfilm and aerosol particles that have a 100% drug purity, therelationship between dose, thickness, and area given above correlatesdirectly to the dose provided to the user. As the percent yield and/orparticle purity decrease, adjustments in the substrate area can be madeas needed to provide the desired dose. Also, as one of skill in the artwill recognize, larger substrate areas other than the minimum calculatedarea for a particular film thickness can be used to deliver atherapeutically effective dose of the drug. Moreover as can beappreciated by one of skill in art, the film need not coat the completesurface area if a selected surface area exceeds the minimum required fordelivering a therapeutic dose from a selected film thickness.

Dosage of Drug Containing Aerosols

The dose of a drug compound or compounds in aerosol form is generally nogreater than twice the standard dose of the drug given orally.Typically, it will be equal to or less than 100% of the standard oraldose. Preferably, it will be less than 80%, and more preferably lessthan 40%, and most preferably less than 20% of the standard oral dose.For medications currently given intravenously, the drug dose in theaerosol will generally be similar to or less than the standardintravenous dose. Preferably it will be less than 200%, more preferablyless than 100%, and most preferably less than 50% of the standardintravenous dose. Oral and/or intravenous doses for most drugs arereadily available in the Physicians Desk Reference.

A dosage of a drug-containing aerosol may be administered in a singleinhalation or may be administered in more than one inhalation, such as aseries of inhalations. Where the drug is administered as a series ofinhalations, the inhalations are typically taken within an hour or less(dosage equals sum of inhaled amounts). When the drug is administered asa series of inhalations, a different amount may be delivered in eachinhalation.

The dose of a drug delivered in the aerosol refers to a unit dose amountthat is generated by heating of the drug under defined conditions,cooling the ensuing vapor, and delivering the resultant aerosol. A “unitdose amount” is the total amount of drug in a given volume of inhaledaerosol. The unit dose amount may be determined by collecting theaerosol and analyzing its composition as described herein, and comparingthe results of analysis of the aerosol to those of a series of referencestandards containing known amounts of the drug. The amount of drug ordrugs required in the starting composition for delivery as a aerosoldepends on the amount of drug or drugs entering the thermal vapor phasewhen heated (i.e., the dose produced by the starting drug or drugs), thebioavailability of the aerosol drug or drugs, the volume of patientinhalation, and the potency of the aerosol drug or drugs as a functionof plasma drug concentration.

One can determine the appropriate dose of a drug-containing aerosol totreat a particular condition using methods such as animal experimentsand a dose-finding (Phase I/II) clinical trial. These experiments mayalso be used to evaluate possible pulmonary toxicity of the aerosol. Oneanimal experiment involves measuring plasma concentrations of drug in ananimal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human and they typically provideaccurate extrapolation of test results to humans. Initial dose levelsfor testing in humans are generally less than or equal to the dose inthe mammal model that resulted in plasma drug levels associated with atherapeutic effect in humans. Dose escalation in humans is thenperformed, until either an optimal therapeutic response is obtained or adose-limiting toxicity is encountered. The actual effective amount ofdrug for a particular patient can vary according to the specific drug orcombination thereof being utilized, the particular compositionformulated, the mode of administration and the age, weight, andcondition of the patient and severity of the episode being treated.

Particle Size

Efficient aerosol delivery to the lungs requires that the particles havecertain penetration and settling or diffusional characteristics.Deposition in the deep lungs occurs by gravitational settling andrequires particles to have an effective settling size, defined as massmedian aerodynamic diameter (MMAD), typically between 1-3.5 μm. Forsmaller particles, deposition to the deep lung occurs by a diffusionalprocess that requires having a particle size in the 10-100 nm, typically20-100 nm range. Particle sizes in the range between 0.1-1.0 μm,however, are generally too small to settle onto the lung wall and toomassive to diffuse to the wall in a timely manner. These types ofparticles are typically removed from the lung by exhalation, and thusare generally not used to treat disease. Therefore, an inhalationdrug-delivery device for deep lung delivery should produce an aerosolhaving particles in one of these two size ranges, preferably betweenabout 1-3 μm MMAD. Typically, in order to produce particles having adesired MMAD, gas or air is passed over the solid support at a certainflow rate.

During the condensation stage the MMAD of the aerosol is increasing overtime. Typically, in variations of the invention, the MMAD increaseswithin the size range of 0.01-3 microns as the vapor condenses as itcools by contact with the carrier gas then further increases as theaerosol particles collide with each other and coagulate into largerparticles. Most typically, the MMAD grows from <0.5 micron to >1 micronin less than 1 second. Thus typically, immediately after condensing intoparticles, the condensation aerosol MMAD doubles at least once persecond, often at least 2, 4, 8, or 20 times per second. In othervariations, the MMAD increases within the size range of 0.1-3 microns.

Typically, the higher the flow rate, the smaller the particles that areformed. Therefore, in order to achieve smaller or larger particles, theflow rate through the condensation region of the delivery device may bealtered. A desired particle size is achieved by mixing a compound in itsvapor-state into a volume of a carrier gas, in a ratio such that thedesired particle size is achieved when the number concentration of themixture reaches approximately 10⁹ particles/mL. The particle growth atthis number concentration is then slow enough to consider the particlesize to be “stable” in the context of a single deep inhalation. This maybe done, for example, by modifying a gas-flow control valve to increaseor decrease the volumetric airflow rate. To illustrate, condensationparticles in the size range 1-3.5 μm MMAD may be produced by selectingthe gas-flow rate to be in a range of 4-50 L/minute, preferably in therange of 5-30 L/min.

Additionally, as will be appreciated by one of skill in the art,particle size may also be altered by modifying the cross-section of thechamber condensation region to increase or decrease linear gas velocityfor a given volumetric flow rate. In addition, particle size may also bealtered by the presence or absence of structures that produce turbulencewithin the chamber. Thus, for example to produce condensation particlesin the size range 10-100 nm MMAD, the chamber may provide gas-flowbarriers for creating air turbulence within the condensation chamber.These barriers are typically placed within a few thousandths of an inchfrom the substrate surface.

Analysis of Drug Containing Aerosols

Purity of a drug-containing aerosol may be determined using a number ofdifferent methods. It should be noted that when the term “purity” isused, it refers to the percentage of aerosol minus the percent byproductproduced in its formation. Byproducts for example, are those unwantedproducts produced during vaporization. For example, byproducts includethermal degradation products as well as any unwanted metabolites of theactive compound or compounds. Examples of suitable methods fordetermining aerosol purity are described in Sekine et al., Journal ofForensic Science 32:1271-1280 (1987) and in Martin et al., Journal ofAnalytic Toxicology 13:158-162 (1989).

One suitable method involves the use of a trap. In this method, theaerosol is collected in a trap in order to determine the percent orfraction of byproduct. Any suitable trap may be used. Suitable trapsinclude filters, glass wool, impingers, solvent traps, cold traps, andthe like. Filters are often most desirable. The trap is then typicallyextracted with a solvent, e.g. acetonitrile, and the extract subjectedto analysis by any of a variety of analytical methods known in the art,for example, gas, liquid, and high performance liquid chromatographyparticularly useful.

The gas or liquid chromatography method typically includes a detectorsystem, such as a mass spectrometry detector or an ultravioletabsorption detector. Ideally, the detector system allows determinationof the quantity of the components of the drug composition and of thebyproduct, by weight. This is achieved in practice by measuring thesignal obtained upon analysis of one or more known mass(es) ofcomponents of the drug composition or byproduct (standards) and thencomparing the signal obtained upon analysis of the aerosol to thatobtained upon analysis of the standard(s), an approach well known in theart.

In many cases, the structure of a byproduct may not be known or astandard for it may not be available. In such cases, one may calculatethe weight fraction of the byproduct by assuming it has an identicalresponse coefficient (e.g. for ultraviolet absorption detection,identical extinction coefficient) to the drug component or components inthe drug composition. When conducting such analysis, byproducts presentin less than a very small fraction of the drug compound, e.g. less than0.1% or 0.03% of the drug compound, are typically excluded. Because ofthe frequent necessity to assume an identical response coefficientbetween drug and byproduct in calculating a weight percentage ofbyproduct, it is often more desirable to use an analytical approach inwhich such an assumption has a high probability of validity. In thisrespect, high performance liquid chromatography with detection byabsorption of ultraviolet light at 225 nm is typically desirable. UVabsorption at 250 nm may be used for detection of compounds in caseswhere the compound absorbs more strongly at 250 nm or for other reasonsone skilled in the art would consider detection at 250 nm the mostappropriate means of estimating purity by weight using HPLC analysis. Incertain cases where analysis of the drug by UV are not viable, otheranalytical tools such as GC/MS or LC/MS may be used to determine purity.

It is possible that modifying the form of the drug may impact the purityof the aerosol obtained. Although not always the case, the free base orfree acid form of the drug as opposed to the salt, generally results ineither a higher purity or yield of the resultant aerosol. Therefore, incertain circumstances, it may be more desirable to use the free base orfree acid forms of the compounds used. Similarly, it is possible thatchanging the gas under which vaporization of the composition occurs mayalso impact the purity.

Other Analytical Methods

Particle size distribution of a drug-containing aerosol may bedetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

Inhalable aerosol mass density may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the inhalation volume of an inhaling patient, typicallyabout 2 liters.

Inhalable aerosol drug mass density may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the inhalation volume of aninhaling patient, typically about 2 liters. The amount of active drugcompound collected in the chamber is determined by extracting thechamber, conducting chromatographic analysis of the extract andcomparing the results of the chromatographic analysis to those of astandard containing known amounts of drug.

Inhalable aerosol particle density may be determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size may be determinedby measuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*(φ/6, whereD is a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²).

Rate of inhalable aerosol particle formation may be determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

Rate of aerosol formation may be determined, for example, by deliveringaerosol phase drug into a confined chamber via an inhalation device. Thedelivery is for a set period of time (e.g., 3 s), and the mass ofparticulate matter collected is determined by weighing the confinedchamber before and after the delivery of the particulate matter. Therate of aerosol formation is equal to the increase in mass in thechamber divided by the duration of the collection time. Alternatively,where a change in mass of the delivery device or component thereof canonly occur through release of the aerosol phase particulate matter, themass of particulate matter may be equated with the mass lost from thedevice or component during the delivery of the aerosol. In this case,the rate of aerosol formation is equal to the decrease in mass of thedevice or component during the delivery event divided by the duration ofthe delivery event.

Rate of drug aerosol formation may be determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is a pure drug, the amount of drug collected in the chamber ismeasured as described above. The rate of drug aerosol formation is equalto the amount of drug collected in the chamber divided by the durationof the collection time. Where the drug-containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of drug in the aerosol provides the rate ofdrug aerosol formation.

Kits

In an embodiment of the invention, a kit is provided for use by ahealthcare provider, or more preferably a patient. The kit fordelivering a condensation aerosol typically comprises a compositioncomprising a drug, and a device for forming a condensation aerosol. Thecomposition is typically void of solvents and excipients and generallycomprises a heat stable drug. The device for forming a condensationaerosol typically comprises an element configured to heat thecomposition to form a vapor, an element allowing the vapor to condenseto form a condensation aerosol, and an element permitting a user toinhale the condensation aerosol. The device in the kit may furthercomprise features such as breath-actuation or lockout elements. Anexemplary kit will provide a hand-held aerosol delivery device and atleast one dose.

In another embodiment, kits for delivering a drug aerosol comprising athin film of a drug composition and a device for dispensing said film asa condensation aerosol are provided. The composition may containpharmaceutical excipients. The device for dispensing said film of a drugcomposition as an aerosol comprises an element configured to heat thefilm to form a vapor, and an element allowing the vapor to condense toform a condensation aerosol.

In the kits of the invention, the composition is typically coated as athin film, generally at a thickness between about 0.5-20 microns, on asubstrate which is heated by a heat source. Heat sources typicallysupply heat to the substrate at a rate that achieves a substratetemperature of at least 200° C., preferably at least 250° C., or morepreferably at least 300° C. or 350° C., and produces substantiallycomplete volatilization of the drug composition from the substratewithin a period of 2 seconds, preferably, within 1 second, or morepreferably within 0.5 seconds. To prevent drug degradation, it ispreferable that the heat source does not heat the substrate totemperature greater than 600° C. while the drug film is on the substrateto prevent. More preferably, the heat source does not heat the substratein to temperatures in excess of 500° C.

The kit of the invention can be comprised of various combinations ofdrugs and drug delivery devices. In some embodiments the device may alsobe present with another drug. The other drug may be administered orallyor topically. Generally, instructions for use are included in the kits.

Utility

As can be appreciated from the above examples showing generation of apure drug condensation aerosol, from thin films (i.e. 0.05-20 μm) of thedrug, the invention finds use in the medical field in compositions andkits for delivery of a drug. Thus, the invention includes, in oneaspect, condensation aerosols.

These aerosols can be used for treating a variety of disease statesand/or intermittent and acute conditions where rapid systemic absorptionand therapeutic effect are highly desirable. Typically the methods oftreatment comprise the step of administering a therapeutically effectiveamount of a drug condensation aerosol to a person with a condition ordisease. Typically the step of administering the drug condensationaerosol comprises the step of administering an orally inhalable drugcondensation aerosol to the person with the condition. The drugcondensation aerosol may be administered in a single inhalation, or inmore than one inhalation, as described above.

The drug condensation aerosol may comprise a drug composition asdescribed above. The drug composition typically is a “heat stable drug”.In some variations, the condensation aerosol comprises at least one drugselected from the group consisting of acebutolol, acetaminophen,alprazolam, amantadine, amitriptyline, apomorphine diacetate,apomorphine hydrochloride, atropine, azatadine, betahistine,brompheniramine, bumetanide, buprenorphine, bupropion hydrochloride,butalbital, butorphanol, carbinoxamine maleate, celecoxib,chlordiazepoxide, chlorpheniramine, chlorzoxazone, ciclesonide,citalopram, clomipramine, clonazepam, clozapine, codeine,cyclobenzaprine, cyproheptadine, dapsone, diazepam, diclofenac ethylester, diflunisal, disopyramide, doxepin, estradiol, ephedrine,estazolam, ethacrynic acid, fenfluramine, fenoprofen, flecainide,flunitrazepam, galanthamine, granisetron, haloperidol, hydromorphone,hydroxychloroquine, ibuprofen, imipramine, indomethacin ethyl ester,indomethacin methyl ester, isocarboxazid, ketamine, ketoprofen,ketoprofen ethyl ester, ketoprofen methyl ester, ketorolac ethyl ester,ketorolac methyl ester, ketotifen, lamotrigine, lidocaine, loperamide,loratadine, loxapine, maprotiline, memantine, meperidine,metaproterenol, methoxsalen, metoprolol, mexiletine HCl, midazolam,mirtazapine, morphine, nalbuphine, naloxone, naproxen, naratriptan,nortriptyline, olanzapine, orphenadrine, oxycodone, paroxetine,pergolide, phenytoin, pindolol, piribedil, pramipexole, procainamide,prochloperazine, propafenone, propranolol, pyrilamine, quetiapine,quinidine, rizatriptan, ropinirole, sertraline, selegiline, sildenafil,spironolactone, tacrine, tadalafil, terbutaline, testosterone,thalidomide, theophylline, tocainide, toremifene, trazodone, triazolam,trifluoperazine, valproic acid, venlafaxine, vitamin E, zaleplon,zotepine, amoxapine, atenolol, benztropine, caffeine, doxylamine,estradiol 17-acetate, flurazepam, flurbiprofen, hydroxyzine, ibutilide,indomethacin norcholine ester, ketorolac norcholine ester, melatonin,metoclopramide, nabumetone, perphenazine, protriptyline HCl, quinine,triamterene, trimipramine, zonisamide, bergapten, chlorpromazine,colchicine, diltiazem, donepezil, eletriptan, estradiol-3,17-diacetate,efavirenz, esmolol, fentanyl, flunisolide, fluoxetine, hyoscyamine,indomethacin, isotretinoin, linezolid, meclizine, paracoxib,pioglitazone, rofecoxib, sumatriptan, tolterodine, tramadol,tranylcypromine, trimipramine maleate, valdecoxib, vardenafil,verapamil, zolmitriptan, zolpidem, zopiclone, bromazepam, buspirone,cinnarizine, dipyridamole, naltrexone, sotalol, telmisartan, temazepam,albuterol, apomorphine hydrochloride diacetate, carbinoxamine,clonidine, diphenhydramine, thambutol, fluticasone proprionate,fluconazole, lovastatin, lorazepam N,O-diacetyl, methadone, nefazodone,oxybutynin, promazine, promethazine, sibutramine, tamoxifen, tolfenamicacid, aripiprazole, astemizole, benazepril, clemastine, estradiol17-heptanoate, fluphenazine, protriptyline, ethambutal, frovatriptan,pyrilamine maleate, scopolamine, and triamcinolone acetonide. In othervariations, the drug is selected from the group consisting ofalprazolam, amoxapine, apomorphine hydrochloride, atropine, bumetanide,buprenorphine, butorphanol, celecoxib, ciclesonide, clomipramine,donepezil, eletriptan, fentanyl, hydromorphone, loxapine, midazolam,morphine, nalbuphine, naratriptan, olanzapine, parecoxib, paroxetine,prochlorperazine, quetiapine, sertraline, sibutramine, sildenafil,sumatriptan, tadalafil, valdecoxib, vardenafil, venlafaxine, andzolpidem. In some variations, the drug condensation aerosol has a MMADin the range of about 1-3 μm.

In another aspect of the invention, kits are provided that include adrug composition and a condensation aerosol delivery device forproduction of a thermal vapor that contains drug-aerosol particles. Thedrug delivery article in the device includes a substrate coated with afilm of a drug composition to be delivered to a subject, preferably ahuman subject. The thickness of the drug composition film is selectedsuch that upon vaporizing the film by heating the substrate to atemperature sufficient to vaporize at least 50% of the drug compositionfilm, typically to a temperature of at least about 200° C., preferablyat least about 250° C., more preferably at least about 300° C. or 350°C., a thermal vapor is generated that has 10% or less drug-degradationproduct. The area of the substrate is selected to provide a therapeuticdose, and is readily determined based on the equations discussed above.

EXAMPLES

The following examples further illustrate the invention described hereinand are in no way intended to limit the scope of the invention.

Materials

Solvents were of reagent grade or better and purchased commercially.

Unless stated otherwise, the drug free base or free acid form was usedin the Examples.

Methods Preparation of Drug-Coating Solution

Drug was dissolved in an appropriate solvent. Common solvent choicesincluded methanol, dichloromethane, methyl ethyl ketone, diethyl ether,3:1 chloroform:methanol mixture, 1:1 dichloromethane: methyl ethylketone mixture, dimethylformamide, and deionized water. Sonicationand/or heat were used as necessary to dissolve the compound. The drugconcentration was typically between 50-200 mg/mL.

Preparation of Drug-Coated Stainless Steel Foil Substrate

Strips of clean 304 stainless steel foil (0.0125 cm thick, Thin MetalSales) having dimensions 1.3 cm by 7.0 cm were dip-coated with a drugsolution as prepared according to Method A. The foil was then partiallydipped three times into solvent to rinse drug off of the last 2-3 cm ofthe dipped end of the foil. Alternatively, the drug coating from thisarea was carefully scraped off with a razor blade. The final coated areawas between 2.0-2.5 cm by 1.3 cm on both sides of the foil, for a totalarea of between 5.2-6.5 cm² Foils were prepared as stated above and thensome were extracted with methanol or acetonitrile as standards. Theamount of drug was determined from quantitative HPLC analysis. Using theknown drug-coated surface area, the thickness was then obtained by:

film thickness(cm)=drug mass(g)/[drug density(g/cm³)×substratearea(cm²).

If the drug density is not known, a value of 1 g/cm³ is assumed. Thefilm thickness in microns is obtained by multiplying the film thicknessin cm by 10,000. After drying, the drug-coated foil was placed into avolatilization chamber constructed of a Delrin® block (the airway) andbrass bars, which served as electrodes. The dimensions of the airwaywere 1.3 cm high by 2.6 cm wide by 8.9 cm long. The drug-coated foil wasplaced into the volatilization chamber such that the drug-coated sectionwas between the two sets of electrodes. After securing the top of thevolatilization chamber, the electrodes were connected to a 1 Faradcapacitor (Phoenix Gold). The back of the volatilization chamber wasconnected to a two micron Teflon® filter (Savillex) and filter housing,which were in turn connected to the house vacuum. Sufficient airflow wasinitiated (typically 30 L/min=1.5 m/sec), at which point the capacitorwas charged with a power supply, typically to between 14-17 Volts. Thecircuit was closed with a switch, causing the drug-coated foil toresistively heat to temperatures of about 280-430° C. (as measured withan infrared camera (FLIR Thermacam SC3000)), in about 200 milliseconds.(For comparison purposes, see FIG. 4A, thermocouple measurement in stillair.) After the drug had vaporized, airflow was stopped and the Teflon®filter was extracted with acetonitrile. Drug extracted from the filterwas analyzed generally by HPLC UV absorbance generally at 225 nm using agradient method aimed at detection of impurities to determine percentpurity. Also, the extracted drug was quantified to determine a percentyield, based on the mass of drug initially coated onto the substrate. Apercent recovery was determined by quantifying any drug remaining on thesubstrate and chamber walls, adding this to the quantity of drugrecovered in the filter and comparing it to the mass of drug initiallycoated onto the substrate.

Preparation of Drug-Coated Aluminum Foil Substrate

A substrate of aluminum foil (10 cm×5.5 cm; 0.0005 inches thick) wasprecleaned with acetone. A solution of drug in a minimal amount ofsolvent was coated onto the foil substrate to cover an area ofapproximately 7-8 cm×2.5 cm. The solvent was allowed to evaporate. Thecoated foil was wrapped around a 300 watt halogen tube (Feit ElectricCompany, Pico Rivera, Calif.), which was inserted into a glass tubesealed at one end with a rubber stopper. Sixty volts of alternatingcurrent (driven by line power controlled by a Variac) were run throughthe bulb for 5-15 seconds, or in some studies 90 V for 3.5-6 seconds, togenerate a thermal vapor (including aerosol) which was collected on theglass tube walls. In some studies, the system was flushed through withargon prior to volatilization. The material collected on the glass tubewalls was recovered and the following determinations were made: (1) theamount emitted, (2) the percent emitted, and (3) the purity of theaerosol by reverse-phase HPLC analysis with detection typically byabsorption of 225 nm light. The initial drug mass was found by weighingthe aluminum foil substrate prior to and after drug coating. The drugcoating thickness was calculated in the same manner as described inMethod B.

Preparation of Drug-Coated Stainless Steel Cylindrical Substrate

A hollow stainless steel cylinder with thin walls, typically 0.12 mmwall thickness, a diameter of 13 mm, and a length of 34 mm was cleanedin dichloromethane, methanol, and acetone, then dried, and fired atleast once to remove any residual volatile material and to thermallypassivate the stainless steel surface. The substrate was then dip-coatedwith a drug coating solution (prepared as disclosed in Method A). Thedip-coating was done using a computerized dip-coating machine to producea thin layer of drug on the outside of the substrate surface. Thesubstrate was lowered into the drug solution and then removed from thesolvent at a rate of typically 5-25 cm/sec. (To coat larger amounts ofmaterial on the substrate, the substrate was removed more rapidly fromthe solvent or the solution used was more concentrated.) The substratewas then allowed to dry for 30 minutes inside a fume hood. If eitherdimethylformamide (DMF) or a water mixture was used as a dip-coatingsolvent, the substrate was vacuum dried inside a desiccator for aminimum of one hour. The drug-coated portion of the cylinder generallyhas a surface area of 8 cm². By assuming a unit density for the drug,the initial drug coating thickness was calculated. The amount of drugcoated onto the substrates was determined in the same manner as thatdescribed in Method B: the substrates were coated, then extracted withmethanol or acetonitrile and analyzed with quantitative HPLC methods, todetermine the mass of drug coated onto the substrate.

The drug-coated substrate was placed in a surrounding glass tubeconnected at the exit end via Tygon® tubing to a filter holder fittedwith a Teflon® filter (Savillex). The junction of the tubing and thefilter was sealed with paraffin film. The substrate was placed in afitting for connection to two 1 Farad capacitors wired in parallel andcontrolled by a high current relay. The capacitors were charged by aseparate power source to about 18-22 Volts and most of the power waschanneled to the substrate by closing a switch and allowing thecapacitors to discharge into the substrate. The substrate was heated toa temperature of between about 300-500° C. (see FIGS. 5A & 5B) in about100 milliseconds. The heating process was done under an airflow of 15L/min, which swept the vaporized drug aerosol into a 2 micron Teflon®filter.

After volatilization, the aerosol captured on the filter was recoveredfor quantification and analysis. The quantity of material recovered inthe filter was used to determine a percent yield, based on the mass ofdrug coated onto the substrate. The material recovered in the filter wasalso analyzed generally by HPLC UV absorbance at typically 225 nm usinga gradient method aimed at detection of impurities, to determine purityof the thermal vapor. Any material deposited on the glass sleeve orremaining on the substrate was also recovered and quantified todetermine a percent total recovery ((mass of drug in filter+mass of drugremaining on substrate and glass sleeve)/mass of drug coated ontosubstrate). For compounds without UV absorption GC/MS or LC/MS was usedto determine purity and to quantify the recovery. Some samples werefurther analyzed by LC/MS to confirm the molecular weight of the drugand any degradants.

Preparation of Drug-Coated Stainless Steel Cylindrical Substrate

A hollow stainless steel cylinder like that described in Example D wasprepared, except the cylinder diameter was 7.6 mm and the length was 51mm. A film of a selected drug was applied as described in Example D.

Energy for substrate heating and drug vaporization was supplied by twocapacitors (1 Farad and 0.5 Farad) connected in parallel, charged to20.5 Volts. The airway, airflow, and other parts of the electrical setup were as described in Example D. The substrate was heated to atemperature of about 420° C. in about 50 milliseconds. After drug filmvaporization, percent yield, percent recovery, and purity analysis weredone as described in Example D.

Preparation of Drug-Coated Aluminum Foil Substrate

A solution of drug (prepared as described in Method A) was coated onto asubstrate of aluminum foil (5 cm²-150 cm²; 0.0005 inches thick). In somestudies, the drug was in a minimal amount of solvent, which was allowedto evaporate. The coated foil was inserted into a glass tube in afurnace (tube furnace). A glass wool plug was placed in the tubeadjacent to the foil sheet and an air flow of 2 L/min was applied. Thefurnace was heated to 200-550° C. for 30, 60, or 120 seconds. Thematerial collected on the glass wool plug was recovered and analyzed byreverse-phase HPLC analysis with detection typically by absorption of225 nm light or GC/MS to determine the purity of the aerosol.

Preparation of Drug-Coated Aluminum Foil Substrate

A substrate of aluminum foil (3.5 cm×7 cm; 0.0005 inches thick) wasprecleaned with acetone. A solution of drug in a minimal amount ofsolvent was coated onto the foil substrate. The solvent was allowed toevaporate. The coated foil was wrapped around a 300 watt halogen tube(Feit Electric Company, Pico Rivera, Calif.), which was inserted into aT-shaped glass tube sealed at two ends with parafilm. The parafilm waspunctured with ten to fifteen needles for air flow. The third openingwas connected to a 1 liter, 3-neck glass flask. The glass flask wasfurther connected to a piston capable of drawing 1.1 liters of airthrough the flask. Ninety volts of alternating current (driven by linepower controlled by a Variac) was run through the bulb for 6-7 secondsto generate a thermal vapor (including aerosol) which was drawn into the1 liter flask. The aerosol was allowed to sediment onto the walls of the1 liter flask for 30 minutes. The material collected on the flask wallswas recovered and the following determinations were made: (1) the amountemitted, (2) the percent emitted, and (3) the purity of the aerosol byreverse-phase HPLC analysis with detection by typically by absorption of225 nm light. Additionally, any material remaining on the substrate wascollected and quantified.

Example 1

Acebutolol (MW 336, melting point 123° C., oral dose 400 mg), abeta-adrenergic blocker (cardiovascular agent), was coated on astainless steel cylinder (8 cm²) according to Method D. 0.89 mg of drugwas applied to the substrate, for a calculated drug film thickness of1.1 μm. The substrate was heated as described in Method D at 20.5 V andpurity of the drug-aerosol particles was determined to be 98.9%. 0.53 mgwas recovered from the filter after vaporization, for a percent yield of59.6%. A total mass of 0.81 mg was recovered from the test apparatus andsubstrate, for a total recovery of 91%. High speed photographs weretaken as the drug-coated substrate was heated to monitor visuallyformation of a thermal vapor. The photographs showed that a thermalvapor was initially visible 30 milliseconds after heating was initiated,with the majority of the thermal vapor formed by 130 milliseconds.Generation of the thermal vapor was complete by 500 milliseconds.

Example 2

Acetaminophen (MW 151, melting point 171° C., oral dose 650 mg), ananalgesic agent, was coated on an aluminum foil substrate (20 cm²)according to Method C. 2.90 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.5 μm. The substrate washeated under argon as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles were determined to be >99.5%. 1.9mg was recovered from the glass tube walls after vaporization, for apercent yield of 65.5%.

Example 3

Albuterol (MW 239, melting point 158° C., oral dose 0.18 mg), abronchodilator, was coated onto six stainless steel foil substrates (5cm²) according to Method B. The calculated thickness of the drug film oneach substrate ranged from about 0.5 μm to about 1.6 μm. The substrateswere heated as described in Method B by charging the capacitors to 15 V.Purity of the drug-aerosol particles from each substrate was determinedand the results are shown in FIG. 23.

Albuterol was also coated on a stainless steel cylinder (8 cm²)according to Method D. 1.20 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.5 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 94.4%. 0.69 mg wasrecovered from the filter after vaporization, for a percent yield of57.2%. A total mass of 0.9 mg was recovered from the test apparatus andsubstrate, for a total recovery of 73.5%.

Example 4

Alprazolam (MW 309, melting point 229° C., oral dose 0.25 mg), ananti-anxiety agent (Xanax®), was coated onto 13 stainless steel cylindersubstrates (8 cm²) according to Method D. The calculated thickness ofthe drug film on each substrate ranged from about 0.1 μm to about 1.4μm. The substrates were heated as described in Method D by charging thecapacitors to 20.5 V. Purity of the drug-aerosol particles from eachsubstrate was determined and the results are shown in FIG. 21.

Another substrate (stainless steel cylinder, 8 cm²) was coated with 0.92mg of drug, for a calculated drug film thickness of 1.2 μm. Thesubstrate was heated as described in Method D by charging the capacitorsto 22.5 V. Purity of the drug-aerosol particles was 99.8%. 0.61 mg wasrecovered from the filter after vaporization, for a percent yield of66.2%. A total mass of 0.92 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Alprazolam was also coated on an aluminum foil substrate (28.8 cm²)according to Method C. 2.6 mg of the drug was coated on the substratefor a calculated thickness of the drug film of 0.9 μm. The substrate washeated substantially as described in Method C at 75 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 99.9%.

High speed photographs were taken as the drug-coated substrate accordingto Method D was heated to monitor visually formation of a thermal vapor.The photographs showed that a thermal vapor was initially visible ˜35milliseconds after heating was initiated, with the majority of thethermal vapor formed by 100 milliseconds. Generation of the thermalvapor was complete by 400 milliseconds.

Example 5

Amantadine (MW 151, melting point 192° C., oral dose 100 mg), adopaminergic agent and an anti-infective agent, was coated on analuminum foil substrate (20 cm²) according to Method C. A mass of 1.6 mgwas coated onto the substrate and the calculated thickness of the drugfilm was 0.8 μm. The substrate was heated as described in Method C at 90V for 4 seconds. The purity of the drug-aerosol particles was determinedto be 100%. 1.5 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 93.8%.

Example 6

Amitriptyline (MW 277, oral dose 50 mg), a tricyclic antidepressant, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 5.2 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 98.4%. 5.3 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of51.5%.

Amitriptyline was also coated on an identical substrate to a thicknessof 1.1 μm. The substrate was heated as described in Method C under anargon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 99.3%. 1.4 mg was recovered from theglass tube walls after vaporization, for a percent yield of 63.6%.

Example 7

Apomorphine diacetate (MW 351), a dopaminergic agent used as ananti-Parkinsonian drug, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method C at 90 V for 3seconds. The purity of the drug-aerosol particles was determined to be96.9%. 2 mg was recovered from the glass tube walls after vaporization,for a percent yield of 90.9%.

Example 8

The hydrochloride salt form of apomorphine was also tested. Apomorphinehydrochloride (MW 304) was coated on a stainless steel foil (6 cm²)according to Method B. 0.68 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.1 μm. The substrate was heated asdescribed in Method B by charging the capacitor to 15 V. The purity ofthe drug-aerosol particles was determined to be 98.1%. 0.6 mg wasrecovered from the filter after vaporization, for a percent yield of88.2%. A total mass of 0.68 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 9

The hydrochloride diacetate salt of apomorphine was also tested (MW388). Apomorphine hydrochloride diacetate was coated on a piece ofaluminum foil (20 cm²) according to Method C. The calculated thicknessof the drug film was 1.0 μm. The substrate was heated as described inMethod C at 90 V for 3 second. purity of the drug-aerosol particles wasdetermined to be 94.0%. 1.65 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 86.8%.

Example 10

Atropine (MW 289, melting point 116° C., oral dose 0.4 mg), anmuscarinic antagonist, was coated on five stainless steel cylindersubstrates (8 cm²) according to Method D. The calculated thickness ofthe drug films ranged from about 1.7 μm to 9.0 μm. The substrate washeated as described in Method D by charging the capacitors to 19 or 22V. Purity of the drug-aerosol particles from each substrate wasdetermined. The results are shown in FIG. 6. For the substrate having adrug film thickness of 1.7 μm, 1.43 mg of drug was applied to thesubstrate. After volatilization of drug from this substrate with acapacitor charged to 22 V, 0.95 mg was recovered from the filter, for apercent yield of 66.6%. The purity of the drug aerosol recovered fromthe filter was found to be 98.5%. A total mass of 1.4 mg was recoveredfrom the test apparatus and substrate, for a total recovery of 98.2%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 28 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by90 milliseconds. Generation of the thermal vapor was complete by 140milliseconds.

Example 11

Azatadine (MW 290, melting point 126° C., oral dose 1 mg), anantihistamine, was coated on an aluminum foil substrate (20 cm²)according to Method C. 5.70 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.9 μm. The substrate washeated as described in Method C at 60 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be 99.6%. 2.8 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of49.1%. Another azatadine-coated substrate was prepared according toMethod G. The substrate was heated as described in Method G at 60 V for6 seconds under an argon atmosphere. The purity of the drug-aerosolparticles was determined to be 99.6%. The percent yield of the aerosolwas 62%.

Example 12

Bergapten (MW 216, melting point 188° C., oral dose 35 mg), ananti-psoriatic agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.06 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.3 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 97.8%. 0.72 mg wasrecovered from the filter after vaporization, for a percent yield of67.9%. A total mass of 1.0 mg was recovered from the test apparatus andsubstrate, for a total recovery of 98.1%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 40 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by85 milliseconds. Generation of the thermal vapor was complete by 140milliseconds.

Example 13

Betahistine (MW 136, melting point <25° C., oral dose 8 mg), a vertigoagent, was coated on a metal substrate according to Method F and heatedto 300° C. to form drug-aerosol particles. Purity of the drug-aerosolparticles was determined to be 99.3%. 17.54 mg was recovered from theglass wool after vaporization, for a percent yield of 58.5%.

Example 14

Brompheniramine (MW 319, melting point <25° C., oral dose 4 mg), ananti-histamine agent, was coated on an aluminum foil substrate (20 cm²)according to Method C. 4.50 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.3 μm. The substrate washeated as described in Method C at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 99.8%. 3.12 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of69.3%. An identical substrate with the same thickness of brompheniramine(4.5 mg drug applied to substrate) was heated under an argon atmosphereat 60 V for 8 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.9%. 3.3 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 73.3%.

The maleate salt form of the drug was also tested. Brompheniraminemaleate (MW 435, melting point 134° C., oral dose 2 mg) was coated ontoan aluminum foil substrate (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.8 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 99.6%. 3.4 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of60.7%. An identical substrate with a 3.2 μm brompheniramine maleate filmwas heated under an argon atmosphere at 60 V for 7 seconds. The purityof the drug-aerosol particles was determined to be 100%. 3.2 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 50%.

Example 15

Bumetanide (MW 364, melting point 231° C., oral dose 0.5 mg), acardiovascular agent and diuretic, was coated on a stainless steelcylinder (8 cm²) according to Method D. 1.09 mg of drug was applied tothe substrate, for a calculated drug film thickness of 1.3 μm. Thesubstrate was heated as described in Method D by charging the capacitorsto 20.5 V. The purity of the drug-aerosol particles was determined to be98.4%. 0.56 mg was recovered from the filter after vaporization, for apercent yield of 51.4%. A total mass of 0.9 mg was recovered from thetest apparatus and substrate, for a total recovery of 82.6%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 40 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by300 milliseconds. Generation of the thermal vapor was complete by 1200milliseconds.

Example 16

Buprenorphine (MW 468, melting point 209° C., oral dose 0.3 mg), ananalgesic narcotic, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 0.7μm. The substrate was heated as described in Method C at 60 V for 5seconds. The purity of the drug-aerosol particles was determined to be98%. 1.34 mg was recovered from the glass tube walls after vaporization,for a percent yield of 95.7%.

Buprenorphine was also coated onto five stainless steel cylindersubstrates (8 cm²) according to Method D except that a 1.5 Faradcapacitor was used as opposed to a 2.0 Farad capacitor. The calculatedthickness of the drug film on each substrate ranged from about 0.3 μm toabout 1.5 μm. The substrates were heated as described in Method D (withthe single exception that the circuit capacitance was 1.5 Farad, not 2.0Farad) and purity of the drug-aerosol particles determined. The resultsare shown in FIG. 9. For the substrate having a 1.5 μm drug film, 1.24mg of drug was applied to the substrate. After volatilization of drugfrom this substrate by charging the capacitors to 20.5 V, 0.865 mg wasrecovered from the filter, for a percent yield of 69.5%. A total mass of1.2 mg was recovered from the test apparatus and substrate, for a totalrecovery of 92.9%. The purity of the drug aerosol recovered from thefilter was determined to be 97.1%.

High speed photographs were taken as one of the drug-coated substrateswas heated, to monitor visually formation of a thermal vapor. Thephotographs, shown in FIGS. 26A-26E, showed that a thermal vapor wasinitially visible 30 milliseconds after heating was initiated, with themajority of the thermal vapor formed by 120 milliseconds. Generation ofthe thermal vapor was complete by 300 milliseconds.

The salt form of the drug, buprenorphine hydrochloride (MW 504), wasalso tested. The drug was coated on a piece of aluminum foil (20 cm²)according to Method C. 2.10 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.1 μm. The substrate washeated as described in Method C at 60 V for 15 seconds. The purity ofthe drug-aerosol particles was determined to be 91.4%. 1.37 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 65.2%. Buprenorphine was further coated on an aluminum foilsubstrate (24.5 cm²) according to Method G. 1.2 mg of the drug wasapplied to the substrate, for a calculated thickness of the drug film of0.49 μm. The substrate was heated substantially as described in Method Gat 90 V for 6 seconds, except that two of the openings of the T-shapedtube were left open and the third connected to the 1 L flask. The purityof the drug-aerosol particles was determined to be >99%. 0.7 mg of thedrug was found to have aerosolized, for a percent yield of 58%.

Example 17

Bupropion hydrochloride (MW 276, melting point 234° C., oral dose 100mg), an antidepressant psychotherapeutic agent, was coated on a piece ofaluminum foil (20 cm²) according to Method C. The calculated thicknessof the drug film was 1.2 μm. The substrate was heated as described inMethod C at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 98.5%. 2.1 mg was recovered from theglass tube walls after vaporization, for a percent yield of 91.3%. Anidentical substrate having the same drug film thickness was heated underan argon atmosphere according to Method C at 90 V for 3.5 seconds. 1.8mg was recovered from the glass tube walls after vaporization, for apercent yield of 78.3%. The recovered vapor had a purity of 99.1%.

Example 18

Butalbital (MW 224, melting point 139° C., oral dose 50 mg), a sedativeand hypnotic barbituate, was coated on a piece of aluminum foil (20 cm²)according to Method C. 2.3 mg were coated on the foil, for a calculatedthickness of the drug film of 1.2 μm. The substrate was heated asdescribed in Method C at 90 V for 3.5 seconds. The purity of thedrug-aerosol particles was determined to be >99.5%. 1.69 mg werecollected for a percent yield of 73%.

Example 19

Butorphanol (MW 327, melting point 217° C., oral dose 1 mg), ananalgesic narcotic agent, was coated on a piece of aluminum foil (20cm²) according to Method C. The calculated thickness of the drug filmwas 1.0 μm. The substrate was heated as described in Method C at 90 Vfor 3.5 seconds. The purity of the drug-aerosol particles was determinedto be 98.7%.

Butorphanol was also coated on a stainless steel cylinder (6 cm²)according to Method E. 1.24 mg of drug was applied to the substrate, fora calculated drug film thickness of 2.1 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 99.4%. 0.802 mg was recovered from the filter aftervaporization, for a percent yield of 64.7%. A total mass of 1.065 mg wasrecovered from the test apparatus and substrate, for a total recovery of85.9%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by60 milliseconds. Generation of the thermal vapor was complete by 90milliseconds.

Example 20

Carbinoxamine (MW 291, melting point <25° C., oral dose 2 mg), anantihistamine, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. 5.30 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 2.7 μm. The substrate washeated as described in Method C at 60 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be 92.5%. 2.8 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of52.8%. A second substrate was coated with carbinoxamine (6.5 mg drug) toa thickness of 3.3 μm. The substrate was heated as described in Method Cat 90 V for 6 seconds under an argon atmosphere. The purity of thedrug-aerosol particles determined was to be 94.8%. 3.1 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of47.7%.

The maleate salt form of the drug was also tested. Carbinoxamine maleate(MW 407, melting point 119° C., oral dose 4 mg) was coated on a piece ofaluminum foil (20 cm²) according to Method C. The calculated thicknessof the drug film was 3.9 μm. The substrate was heated as described inMethod C at 90 V for 6 seconds. The purity of the drug-aerosol particleswas determined to be 99%. 4.8 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 62.3%.

Example 21

Celecoxib (MW 381, melting point 159° C., oral dose 100 mg), ananalgesic non-steroidal anti-inflammatory agent, was coated on a pieceof stainless steel foil (5 cm²) according to Method B. 4.6 mg of drugwas applied to the substrate, for a calculated drug film thickness of8.7 μm. The substrate was heated as described in Method B by chargingthe capacitors to 16 V. The purity of the drug-aerosol particles wasdetermined to be >99.5%. 4.5 mg was recovered from the filter aftervaporization, for a percent yield of 97.8%. A total mass of 4.6 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Celecoxib was also coated on a piece of aluminum foil (100 cm²)according to Method G. The calculated thickness of the drug film was 3.1μm. The substrate was heated as described in Method G at 60 V for 15seconds. The purity of the drug-aerosol particles was determined to be99%. 24.5 mg was recovered from the glass tube walls after vaporization,for a percent yield of 79%.

Example 22

Chlordiazepoxide (MW 300, melting point 237° C., oral dose 5 mg), asedative and hypnotic agent, was coated on a piece of aluminum foil (20cm²) according to Method C. The calculated thickness of the drug filmwas 2.3 μm. The substrate was heated as described in Method C at 45 Vfor 15 seconds. The purity of the drug-aerosol particles was determinedto be 98.2%. 2.5 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 54.3%.

Example 23

Chlorpheniramine (MW 275, melting point <25° C., oral dose 4 mg), anantihistamine, was coated onto an aluminum foil substrate (20 cm²)according to Method C. 5.90 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 3 μm. The substrate washeated as described in Method C at 60 V for 10 seconds. The purity ofthe drug-aerosol particles was determined to be 99.8%. 4.14 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 70.2%. The maleate salt form (MW 391, melting point 135° C.,oral dose 8 mg) was coated on an identical substrate to a thickness of1.6 μm. The substrate was heated as described in Method C at 60 V for 7seconds. The purity of the drug-aerosol particles was determined to be99.6%. 2.1 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 65.6%.

Example 24

Chlorpromazine (MW 319, melting point <25° C., oral dose 300 mg), anantipsychotic, psychotherapeutic agent, was coated on an aluminum foilsubstrate (20 cm²) according to Method C. 9.60 mg of drug was applied tothe substrate, for a calculated thickness of the drug film of 4.8 μm.The substrate was heated as described in Method C at 90 V for 5 seconds.The purity of the drug-aerosol particles was determined to be 96.5%. 8.6mg was recovered from the glass tube walls after vaporization, for apercent yield of 89.6%.

Example 25

Chlorzoxazone (MW 170, melting point 192° C., oral dose 250 mg), amuscle relaxant, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.3μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be99.7%. 1.55 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 59.6%.

Example 26

Ciclesonide (MW 541, melting point 206.5-207° C., oral dose 0.2 mg) aglucocorticoid, was coated on stainless steel foil substrates (6 cm²)according to Method B. Eight substrates were prepared, with the drugfilm thickness ranging from about 0.4 μm to about 2.4 μm. The substrateswere heated as described in Method B, with the capacitors charged with15.0 or 15.5 V. Purity of the drug-aerosol particles from each substratewas determined and the results are shown in FIG. 11. The substratehaving a thickness of 0.4 μm was prepared by depositing 0.204 mg drug onthe substrate surface. After volatilization of drug from this substrateusing capacitors charged to 15.0 V, 0.201 mg was recovered from thefilter, for a percent yield of 98.5%. The purity of the drug aerosolparticles was determined to be 99%. A total mass of 0.204 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Example 27

Citalopram (MW 324, melting point <25° C., oral dose 20 mg), apsychotherapeutic agent, was coated onto an aluminum foil substrate (20cm²) according to Method C. 8.80 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 4.4 μm. Thesubstrate was heated as described in Method C at 90 V for 4 seconds. Thepurity of the drug-aerosol particles was determined to be 92.3%. 5.5 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 62.5%. Another substrate containing citalopram coated(10.10 mg drug) to a film thickness of 5 μm was prepared by the samemethod and heated under an argon atmosphere. The purity of thedrug-aerosol particles was determined to be 98%. 7.2 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of71.3%.

Example 28

Clomipramine (MW 315, melting point <25° C., oral dose 150 mg), apsychotherapeutic agent, was coated onto eight stainless steelcylindrical substrates according to Method E. The calculated thicknessof the drug film on each substrate ranged from about 0.8 μm to about 3.9μm. The substrates were heated as described in Method E and purity ofthe drug-aerosol particles determined. The results are shown in FIG. 10.For the substrate having a drug film thickness of 0.8 μm, 0.46 mg ofdrug was applied to the substrate. After volatilization of drug fromthis substrate, 0.33 mg was recovered from the filter, for a percentyield of 71.7%. Purity of the drug-aerosol particles was determined tobe 99.4%. A total mass of 0.406 mg was recovered from the test apparatusand substrate, for a total recovery of 88.3%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 40 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by75 milliseconds. Generation of the thermal vapor was complete by 115milliseconds.

Example 29

Clonazepam (MW 316, melting point 239° C., oral dose 1 mg), ananticonvulsant, was coated on an aluminum foil substrate (50 cm²) andheated according to Method F to a temperature of 350° C. to formdrug-aerosol particles. 46.4 mg of the drug was applied to thesubstrate, for a calculated thickness of the drug film of 9.3 μm. Purityof the drug-aerosol particles was determined to be 14%.

Clonazepam was further coated on an aluminum foil substrate (24 cm²)according to Method C. 5 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 2.1 μm. The substrate washeated substantially as described in Method C at 60 V for 8 seconds. Thepurity of the drug-aerosol particles was determined to be 99.9%.

Example 30

Clonidine (MW 230, melting point 130° C., oral dose 0.1 mg), acardiovascular agent, was coated on an aluminum foil substrate (50 cm²)and heated according to Method F at 300° C. to form drug-aerosolparticles. Purity of the drug-aerosol particles was determined to be94.9%. The yield of aerosol particles was 90.9%.

Example 31

Clozapine (MW 327, melting point 184° C., oral dose 150 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 14.30 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 7.2 μm. Thesubstrate was heated as described in Method C at 90 V for 5 seconds. Thepurity of the drug-aerosol particles was determined to be 99.1%. 2.7 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 18.9%. Another substrate containing clozapine coated(2.50 mg drug) to a film thickness of 1.3 μm was prepared by the samemethod and heated under an argon atmosphere at 90 V for 3.5 seconds. Thepurity of the drug-aerosol particles was determined to be 99.5%. 1.57 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 62.8%.

Example 32

Codeine (MW 299, melting point 156° C., oral dose 15 mg), an analgesic,was coated on an aluminum foil substrate (20 cm²) according to Method C.8.90 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 4.5 μm. The substrate was heated as described inMethod C at 90 V for 5 seconds. The purity of the drug-aerosol particleswas determined to be 98.1%. 3.46 mg was recovered from the glass tubewalls after vaporization, for a percent yield of 38.9%.

Another substrate containing codeine coated (2.0 mg drug) to a filmthickness of 1 μm was prepared by the same method and heated under anargon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be >99.5%. 1 mg was recovered from the glasstube walls after vaporization, for a percent yield of 50%.

Example 33

Colchicine (MW 399, melting point 157° C., oral dose 0.6 mg), a goutpreparation, was coated on a stainless steel cylinder (8 cm²) accordingto Method D. 1.12 mg of drug was applied to the substrate, for acalculated drug film thickness of 1.3 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 97.7%. 0.56 mg wasrecovered from the filter after vaporization, for a percent yield of50%. A total mass of 1.12 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by140 milliseconds. Generation of the thermal vapor was complete by 700milliseconds.

Example 34

Cyclobenzaprine (MW 275, melting point <25° C., oral dose 10 mg), amuscle relaxant, was coated on an aluminum foil substrate (20 cm²)according to Method C. 9.0 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 4.5 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 6.33 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of70.3%.

Example 35

Cyproheptadine (MW 287, melting point 113° C., oral dose 4 mg), anantihistamine, was coated on an aluminum foil substrate (20 cm²)according to Method C. 4.5 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.3 μm. The substrate washeated as described in Method C at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be >99.5%. 3.7 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of82.2%.

Cyproheptadine HCl salt (MW 324, melting point 216° C., oral dose 4 mg)was coated on an identical substrate to a thickness of 2.2 μm. Thesubstrate was heated at 60V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 99.6%. 2.6 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of60.5%.

Example 36

Dapsone (MW 248, melting point 176° C., oral dose 50 mg), ananti-infective agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.92 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be >99.5%. 0.92 mg wasrecovered from the filter after vaporization, for a percent yield of100%. The total mass was recovered from the test apparatus andsubstrate, for a total recovery of about 100%.

Example 37

Diazepam (MW 285, melting point 126° C., oral dose 2 mg), a sedative andhypnotic, was coated on an aluminum foil substrate (20 cm²) according toMethod C. 5.30 mg of drug was applied to the substrate, for a calculatedthickness of the drug film of 2.7 μm. The substrate was heated asdescribed in Method C at 40 V for 17 seconds. The purity of thedrug-aerosol particles was determined to be 99.9%. 4.2 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of79.2%.

Diazepam was also coated on a circular aluminum foil substrate (78.5cm²). 10.0 mg of drug was applied to the substrate, for a calculatedfilm thickness of the drug of 1.27 μm. The substrate was secured to theopen side of a petri dish (100 mm diameter×50 mm height) using parafilm.The glass bottom of the petri dish was cooled with dry ice, and thealuminum side of the apparatus was placed on a hot plate at 240° C. for10 seconds. The material collected on the beaker walls was recovered andanalyzed by HPLC analysis with detection by absorption of 225 nm lightused to determine the purity of the aerosol. Purity of the drug-aerosolparticles was determined to be 99.9%.

Diazepam was also coated on an aluminum foil substrate (36 cm²)according to Method G. 5.1 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.4 μm. The substrate washeated substantially as described in Method G, except that 90 V for 6seconds was used, and purity of the drug-aerosol particles wasdetermined to be 99%. 3.8 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 74.5%.

Example 38

Diclofenac ethyl ester (MW 324, oral dose 50 mg), an antirheumaticagent, was coated on a metal substrate (50 cm²) and heated according toMethod F at 300° C. to form drug-aerosol particles. 50 mg of drug wasapplied to the substrate, for a calculated thickness of the drug film of10 μm. Purity of the drug-aerosol particles was determined to be 100% byGC analysis. The yield of aerosol particles was 80%.

Example 39

Diflunisal (MW 250, melting point 211° C., oral dose 250 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 5.3 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be >99.5%. 5.47mg was recovered from the glass tube walls after vaporization, for apercent yield of 51.6%.

Example 40

Diltiazem (MW 415, oral dose 30 mg), a calcium channel blocker used as acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.8 mg of drug was applied to the substrate, fora calculated drug film thickness of 1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5V. The purity ofthe drug-aerosol particles was determined to be 94.2%. 0.53 mg wasrecovered from the filter after vaporization, for a percent yield of66.3%. A total mass of 0.8 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

The drug was also coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 1.0 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 seconds.The purity of the drug-aerosol particles was determined to be 85.5%.1.91 mg was recovered from the glass tube walls after vaporization, fora percent yield of 95.5%.

Diltiazem was also coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 1.1 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 secondsunder an argon atmosphere. The purity of the drug-aerosol particles wasdetermined to be 97.1%. 1.08 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 49.1%.

Example 41

Diphenhydramine (MW 255, melting point <25° C., oral dose 25 mg), anantihistamine, was coated on an aluminum foil substrate (20 cm²)according to Method C. 5.50 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.8 μm. The substrate washeated as described in Method C at 108 V for 2.25 seconds. The purity ofthe drug-aerosol particles was determined to be 93.8%. 3.97 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 72.2%.

The hydrochloride salt was also tested. 4.90 mg of drug was coated ontoan aluminum substrate, for a calculated thickness of the drug film of2.5 μm. The substrate was heated under an argon atmosphere as describedin Method C at 60 V for 10 seconds. The purity of the drug-aerosolparticles was determined to be 90.3%. 3.70 mg was recovered from theglass tube walls after vaporization, for a percent yield of 75.5%.Another experiment with the hydrochloride salt was done under an argonatmosphere. 5.20 mg of drug was coated onto an aluminum substrate, for acalculated thickness of the drug film of 2.6 μm. The substrate washeated as described in Method C at 60 V for 10 seconds. The purity ofthe drug-aerosol particles was determined to be 93.3%. 3.90 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 75.0%.

Example 42

Disopyramide (MW 339, melting point 95° C., oral dose 100 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.07 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.3 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99%. 0.63 mg wasrecovered from the filter after vaporization, for a percent yield of58.9%. A total mass of 0.9 mg was recovered from the test apparatus andsubstrate, for a total recovery of 84.1%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. Thephotographs, shown in FIGS. 25A-25D, showed that a thermal vapor wasinitially visible 50 milliseconds after heating was initiated, with themajority of the thermal vapor formed by 100 milliseconds. Generation ofthe thermal vapor was complete by 200 milliseconds.

Example 43

Doxepin (MW 279, melting point <25° C. oral dose 75 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.0 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.0 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 99%. The total massrecovered from the glass tube walls after vaporization ˜100%.

Another substrate containing doxepin was also prepared. On an aluminumfoil substrate (20 cm²) 8.6 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 4.5 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 81.1%. 6.4 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of74.4%.

Another substrate containing doxepin was also prepared for testing underargon. On an aluminum foil substrate (20 cm²) 1.8 mg of drug was appliedto the substrate, for a calculated thickness of the drug film of 0.9 μm.The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be99.1%. The total mass recovered from the glass tube walls aftervaporization ˜100%.

Example 44

Donepezil (MW 379, oral dose 5 mg), a drug used in management ofAlzheimer's, was coated on a stainless steel cylinder (8 cm²) accordingto Method D. 5.73 mg of drug was applied to the substrate, for acalculated drug film thickness of 6.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 96.9%. 3 mg wasrecovered from the filter after vaporization, for a percent yield of52.4%. A total mass of 3 mg was recovered from the test apparatus andsubstrate, for a total recovery of 52.4%.

Donepezil was also tested according to Method B, by coating a solutionof the drug onto a piece of stainless steel foil (5 cm²). Six substrateswere prepared, with film thicknesses ranging from about 0.5 μm to about3.2 μm. The substrates were heated as described in Method B by chargingthe capacitors to 14.5 or 15.5 V. Purity of the drug aerosol particlesfrom each substrate was determined. The results are shown in FIG. 7.

Donepezil was also tested by coating a solution of the drug onto a pieceof stainless steel foil (5 cm²). The substrate having a drug filmthickness of 2.8 μm was prepared by depositing 1.51 mg of drug. Aftervolatilization of drug from the substrate by charging the capacitors to14.5 V, 1.37 mg of aerosol particles were recovered from the filter, fora percent yield of 90.9%. The purity of drug compound recovered from thefilter was 96.5%. A total mass of 1.51 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

Example 45

Eletriptan (MW 383, oral dose 3 mg), a serotonin 5-HT receptor agonistused as a migraine preparation, was coated on a piece of stainless steelfoil (6 cm²) according to Method B. 1.38 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 2.2 μm. The substratewas heated as described in Method B by charging the capacitors to 16 V.The purity of the drug-aerosol particles was determined to be 97.8%.1.28 mg was recovered from the filter after vaporization, for a percentyield of 93%. The total mass was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 46

Estradiol (MW 272, melting point 179° C., oral dose 2 mg), a hormonalagent, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 1.3 μm. Thesubstrate was heated as described in Method C at 60 V for 9 seconds. Thepurity of the drug-aerosol particles was determined to be 98.5%. 1.13 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 45.2%.

Another substrate containing estradiol was also prepared for testingunder argon. On an aluminum foil substrate (20 cm²) 2.6 mg of drug wasapplied to the substrate, for a calculated thickness of the drug film of1.3 μm. The substrate was heated as described in Method C at 60 V for 9seconds. The purity of the drug-aerosol particles was determined to be98.7%. 1.68 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 64.6%.

Example 47

Estradiol-3,17-diacetate (MW 357, oral dose 2 mg), a hormonal prodrug,was coated on a piece of aluminum foil (20 cm²) according to Method C.The calculated thickness of the drug film was 0.9 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 96.9%. 1.07 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of62.9%.

Example 48

Efavirenz (MW 316, melting point 141° C., oral dose 600 mg), ananti-infective agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.82 mg of drug was applied to the substrate, fora calculated drug film thickness of 1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 97.9%. 0.52 mg wasrecovered from the filter after vaporization, for a percent yield of63.4%. A total mass of 0.6 mg was recovered from the test apparatus andsubstrate, for a total recovery of 73.2%.

Example 49

Ephedrine (MW 165, melting point 40° C., oral dose 10 mg), a respiratoryagent, was coated on an aluminum foil substrate (20 cm²) according toMethod C. 8.0 mg of drug was applied to the substrate, for a calculatedthickness of the drug film of 4.0 μm. The substrate was heated asdescribed in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 7.26 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of90.8%.

Example 50

Esmolol (MW 295, melting point 50° C., oral dose 35 mg), acardiovascular agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 4.9μm. The substrate was heated as described in Method C at 90 V for 5seconds. The purity of the drug-aerosol particles was determined to be95.8%. 6.4 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 65.3%.

Esmolol was coated on a stainless steel cylinder (8 cm²) according toMethod D. 0 83 mg of drug was applied to the substrate, for a calculateddrug film thickness of 1.4 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 93%. 0.63 mg was recoveredfrom the filter after vaporization, for a percent yield of 75.9%. Atotal mass of 0.81 mg was recovered from the test apparatus andsubstrate, for a total recovery of 97.6%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by60 milliseconds. Generation of the thermal vapor was complete by 75milliseconds.

Example 51

Estazolam (MW 295, melting point 229° C., oral dose 2 mg), a sedativeand hypnotic, was coated on an aluminum foil substrate (20 cm²)according to Method C. 2.0 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.0 μm. The substrate washeated basically as described in Method C at 60 V for 3 seconds then 45V for 11 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.9%. 1.4 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 70%.

Example 52

Ethacrynic acid (MW 303, melting point 122° C., oral dose 25.0 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method E. 1.10 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.3 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 99.8%. 0.85 mg was recovered from the filter aftervaporization, for a percent yield of 77.3%. A total mass of 1.1 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Example 53

Ethambutol (MW 204, melting point 89° C., oral dose 1000 mg), aanti-infective agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.85 mg of drug was applied to the substrate, fora calculated drug film thickness of 1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 90%. 0.50 mg wasrecovered from the filter after vaporization, for a percent yield of58.8%. A total mass of 0.85 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by50 milliseconds. Generation of the thermal vapor was complete by 90milliseconds.

Example 54

Fluticasone propionate (MW 501, melting point 272° C., oral dose 0.04mg), a respiratory agent, was coated on a piece of stainless steel foil(5 cm²) according to Method B. The calculated thickness of the drug filmwas 0.6 μm. The substrate was heated as described in Method B bycharging the capacitors to 15.5 V. The purity of the drug-aerosolparticles was determined to be 91.6%. 0.211 mg was recovered from thefilter after vaporization, for a percent yield of 70.1%. A total mass of0.215 mg was recovered from the test apparatus and substrate, for atotal recovery of 71.4%.

Example 55

Fenfluramine (MW 231, melting point 112° C., oral dose 20 mg), anobesity management, was coated on a piece of aluminum foil (20 cm²)according to Method C. 9.2 mg were coated. The calculated thickness ofthe drug film was 4.6 μm. The substrate was heated as described inMethod C at 90 V for 5 seconds. The purity of the drug-aerosol particleswas determined to be >99.5%. The total mass was recovered from the glasstube walls after vaporization for a percent yield of ˜100%.

Example 56

Fenoprofen (MW 242, melting point <25° C., oral dose 200 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 3.7 μm. Thesubstrate was heated as described in Method C at 60 V for 5 seconds. Thepurity of the drug-aerosol particles was determined to be 98.7%. 4.98 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 67.3%.

Example 57

Fentanyl (MW 336, melting point 84° C., oral dose 0.2 mg), an analgesic,was coated onto ten stainless steel foil substrates (5 cm²) according toMethod B. The calculated thickness of the drug film on each substrateranged from about 0.2 μm to about 3.3 μm. The substrates were heated asdescribed in Method B by charging the capacitors to 14 V. Purity of thedrug-aerosol particles from each substrate was determined and theresults are shown in FIG. 20.

Fentanyl was also coated on a stainless steel cylinder (8 cm²) accordingto Method D. 0.29 mg of drug was applied to the substrate, for acalculated drug film thickness of 0.4 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 18 V. The purity ofthe drug-aerosol particles was determined to be 97.9%. 0.19 mg wasrecovered from the filter after vaporization, for a percent yield of64%. A total mass of 0.26 mg was recovered from the test apparatus andsubstrate, for a total recovery of 89%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by100 milliseconds. Generation of the thermal vapor was complete by 250milliseconds.

Example 58

Flecainide (MW 414, oral dose 50 mg), a cardiovascular agent, was coatedon a stainless steel cylinder (8 cm²) according to Method D. 0.80 mg ofdrug was applied to the substrate, for a calculated drug film thicknessof 1 μm. The substrate was heated as described in Method D by chargingthe capacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 99.6%. 0.54 mg was recovered from the filter aftervaporization, for a percent yield of 67.5%. A total mass of 0.7 mg wasrecovered from the test apparatus and substrate, for a total recovery of90%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by65 milliseconds. Generation of the thermal vapor was complete by 110milliseconds.

Example 59

Fluconazole (MW 306, melting point 140° C., oral dose 200 mg), ananti-infective agent, was coated on a piece of stainless steel foil (5cm²) according to Method B. 0.737 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 1.4 μm. The substratewas heated as described in Method B by charging the capacitors to 15.5V. The purity of the drug-aerosol particles was determined to be 94.3%.0.736 mg was recovered from the filter after vaporization, for a percentyield of 99.9%. A total mass of 0.737 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

Example 60

Flunisolide (MW 435, oral dose 0.25 mg), a respiratory agent, was coatedwas coated on a stainless steel cylinder (8 cm²) according to Method E.0.49 mg of drug was applied to the substrate, for a calculated drug filmthickness of 0.6 μm. The substrate was heated as described in Method Eand purity of the drug-aerosol particles was determined to be 97.6%. 0.3mg was recovered from the filter after vaporization, for a percent yieldof 61.2%. A total mass of 0.49 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

Another substrate (stainless steel foil, 5 cm²) was prepared by applying0.302 mg drug to form a film having a thickness of 0.6 μm. The substratewas heated as described in Method B by charging the capacitor to 15.0 V.The purity of the drug-aerosol particles was determined to be 94.9%.0.296 mg was recovered from the filter after vaporization, for a percentyield of 98%. A total mass of 0.302 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

Example 61

Flunitrazepam (MW 313, melting point 167° C., oral dose 0.5 mg), asedative and hypnotic, was coated on a piece of aluminum foil (24.5 cm²)according to Method G. The calculated thickness of the drug film was 0.6μm. The substrate was heated as described in Method G at 90 V for 6seconds. The purity of the drug-aerosol particles was determined to be99.8%. 0.73 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 60.8%.

Flunitrazepam was further coated on an aluminum foil substrate (24 cm²)according to Method C. 5 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 2.08 μm. The substratewas heated substantially as described in Method C at 60 V for 7 seconds.The purity of the drug-aerosol particles was determined to be at least99.9%.

Example 62

Fluoxetine (MW 309, oral dose 20 mg), a psychotherapeutic agent, wascoated on an aluminum foil substrate (20 cm²) according to Method C.1.90 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 1.0 μm. The substrate was heated as described inMethod C at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 97.4%. 1.4 mg was recovered from theglass tube walls after vaporization, for a percent yield of 73.7%.

Another substrate containing fluoxetine coated (2.0 mg drug) to a filmthickness of 1.0 μm was prepared by the same method and heated under anargon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 96.8%. 1.7 mg was recovered from theglass tube walls after vaporization, for a percent yield of 85.0%.

Example 63

Galanthamine (MW 287, oral dose 4 mg) was coated on a stainless steelcylinder (8 cm²) according to Method D. 1.4 mg of drug was applied tothe substrate, for a calculated drug film thickness of 1.7 μm. Thesubstrate was heated as described in Method D by charging the capacitorsto 20.5 V. The purity of the drug-aerosol particles was determined tobe >99.5%. 1.16 mg was recovered from the filter after vaporization, fora percent yield of 82.6%. A total mass of 1.39 mg was recovered from thetest apparatus and substrate, for a total recovery of 99.1%.

Example 64

Granisetron (MW 312, oral dose 1 mg), a gastrointestinal agent, wascoated on an aluminum foil substrate (20 cm²) according to Method C.1.50 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 0.8 μm. The substrate was heated as described inMethod C at 30 V for 45 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 1.3 mg was recovered from the glasstube walls after vaporization, for a percent yield of 86.7%.

1.10 mg of granisetron was also coated on an aluminum foil substrate(24.5 cm²) to a calculated drug film thickness of 0.45 μm. The substratewas heated substantially as described in Method G at 90 V for 6 seconds.The purity of the drug-aerosol particles was determined to be 93%. 0.4mg was recovered from the glass tube walls, for a percent yield of 36%.

Example 65

Haloperidol (MW 376, melting point 149° C., oral dose 2 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.20 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 1.1 μm. Thesubstrate was heated as described in Method C at 108 V for 2.25 seconds.The purity of the drug-aerosol particles was determined to be 99.8%. 0.6mg was recovered from the glass tube walls after vaporization, for apercent yield of 27.3%.

Haloperidol was further coated on an aluminum foil substrate accordingto Method C. The substrate was heated as described in Method C. When 2.1mg of the drug was heated at 90 V for 3.5 seconds, the purity of theresultant drug-aerosol particles was determined to be 96%. 1.69 mg ofaerosol particles were collected for a percent yield of the aerosol of60%. When 2.1 mg of drug was used and the system was flushed with argonprior to volatilization, the purity of the drug-aerosol particles wasdetermined to be 97%. The percent yield of the aerosol was 29%.

Example 66

Hydromorphone (MW 285, melting point 267° C., oral dose 2 mg), ananalgesic, was coated on a stainless steel cylinder (9 cm²) according toMethod D. 5.62 mg of drug was applied to the substrate, for a calculateddrug film thickness of 6.4 μm. The substrate was heated as described inMethod D by charging the capacitors to 19 V. The purity of thedrug-aerosol particles was determined to be 99.4%. 2.34 mg was recoveredfrom the filter after vaporization, for a percent yield of 41.6%. Atotal mass of 5.186 mg was recovered from the test apparatus andsubstrate, for a total recovery of 92.3%.

Hydromorphone was also coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be98.3%. 0.85 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 40.5%.

Hydromorphone was also coated onto eight stainless steel cylindersubstrates (8 cm²) according to Method D. The calculated thickness ofthe drug film on each substrate ranged from about 0.7 μm to about 2.8μm. The substrates were heated as described in Method D by charging thecapacitors to 20.5 V. The purity of the drug-aerosol particlesdetermined. The results are shown in FIG. 8. For the substrate having adrug film thickness of 1.4 μm, 1.22 mg of drug was applied to thesubstrate. After vaporization of this substrate, 0.77 mg was recoveredfrom the filter, for a percent yield of 63.21%. The purity of thedrug-aerosol particles was determined to be 99.6%. A total mass of 1.05mg was recovered from the test apparatus and substrate, for a totalrecovery of 86.1%.

Example 67

Hydroxychloroquine (MW 336, melting point 91° C., oral dose 400 mg), anantirheumatic agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 6.58 mg of drug was applied to the substrate, fora calculated drug film thickness of 11 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 98.9%. 3.48 mg wasrecovered from the filter after vaporization, for a percent yield of52.9%. A total mass of 5.1 mg was recovered from the test apparatus andsubstrate, for a total recovery of 77.8%.

Example 68

Hyoscyamine (MW 289, melting point 109° C., oral dose 0.38 mg), agastrointestinal agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 0.9μm. The substrate was heated as described in Method C at 60 V for 8seconds. The purity of the drug-aerosol particles was determined to be95.9%. 0.86 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 50.6%.

Example 69

Ibuprofen (MW 206, melting point 77° C., oral dose 200 mg), ananalgesic, was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 10.20 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 5.1 μm. The substrate washeated as described in Method C at 60 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 99.7%. 5.45 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of53.4%.

Example 70

Imipramine (MW 280, melting point <25° C., oral dose 50 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. 1.8 mg was coated on the aluminum foil. Thecalculated thickness of the drug film was 0.9 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 98.3%. The total massrecovered from the glass tube walls after vaporization was ˜100%.

Another substrate containing imipramine coated to a film thickness of0.9 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 99.1%. 1.5 mg was recovered from theglass tube walls after vaporization, for a percent yield of 83.3%.

Example 71

Indomethacin (MW 358, melting point 155° C., oral dose 25 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 1.2 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 96.8%. 1.39 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 60.4%.

Another substrate containing indomethacin coated to a film thickness of1.5 μm was prepared by the same method and heated under an argonatmosphere at 60 V for 6 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 0.61 mg was recovered from the glasstube walls after vaporization, for a percent yield of 20.3%.

Example 72

Indomethacin ethyl ester (MW 386, oral dose 25 mg), an analgesic, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.6 μm. The substrate washeated as described in Method C at 60 V for 9 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 2.23 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of42.9%.

Another substrate containing indomethacin ethyl ester coated to a filmthickness of 2.6 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 9 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 3.09 mg was recovered from the glasstube walls after vaporization, for a percent yield of 59.4%.

Example 73

Indomethacin methyl ester (MW 372, oral dose 25 mg), an analgesic, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.1 μm. The substrate washeated as described in Method C at 60 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 1.14 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of27.1%.

Another substrate containing indomethacin methyl ester coated to a filmthickness of 1.2 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 6 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 1.44 mg was recovered from the glasstube walls after vaporization, for a percent yield of 60%.

Example 74

Isocarboxazid (MW 231, melting point 106° C., oral dose 10 mg), apsychotherapeutic agent, was coated on a stainless steel cylinder (8cm²) according to Method D. 0.97 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 1.2 μm. The substratewas heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 99.6%.0.52 mg was recovered from the filter after vaporization, for a percentyield of 53%. A total mass of 0.85 mg was recovered from the testapparatus and substrate, for a total recovery of 87.7%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by70 milliseconds. Generation of the thermal vapor was complete by 200milliseconds.

Example 75

Isotretinoin (MW 300, melting point 175° C., oral dose 35 mg), a skinand mucous membrane agent, was coated on a stainless steel cylinder (8cm²) according to Method D. 1.11 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 1.4 μm. The substratewas heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 96.6%.0.66 mg was recovered from the filter after vaporization, for a percentyield of 59.5%. A total mass of 0.86 mg was recovered from the testapparatus and substrate, for a total recovery of 77.5%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by65 milliseconds. Generation of the thermal vapor was complete by 110milliseconds.

Example 76

Ketamine (MW 238, melting point 93° C., IV dose 100 mg), an anesthetic,was coated on a stainless steel cylinder (8 cm²) according to Method D.0.836 mg of drug was applied to the substrate, for a calculated drugfilm thickness of 1.0 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 99.9%. 0.457 mg wasrecovered from the filter after vaporization, for a percent yield of54.7%. A total mass of 0.712 mg was recovered from the test apparatusand substrate, for a total recovery of 85.2%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by75 milliseconds. Generation of the thermal vapor was complete by 100milliseconds.

Example 77

Ketoprofen (MW 254, melting point 94° C., oral dose 25 mg), ananalgesic, was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 10.20 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 5.1 μm. The substrate washeated as described in Method C at 60 V for 16 seconds. The purity ofthe drug-aerosol particles was determined to be 98%. 7.24 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 71%.

Example 78

Ketoprofen ethyl ester (MW 282, oral dose 25 mg), an analgesic, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.0 μm. The substrate washeated as described in Method C at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 3.52 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of88%.

Another substrate containing ketroprofen ethyl ester coated to a filmthickness of 2.7 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 8 seconds. The purity of the drug-aerosolparticles was determined to be 99.6%. 4.1 mg was recovered from theglass tube walls after vaporization, for a percent yield of 77.4%.

Example 79

Ketoprofen Methyl Ester (MW 268, oral dose 25 mg), an analgesic, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.0 μm. The substrate washeated as described in Method C at 60 V for 8 seconds purity of thedrug-aerosol particles was determined to be 99%. 2.25 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of56.3%.

Another substrate containing ketoprofen methyl ester coated to a filmthickness of 3.0 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 8 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 4.4 mg was recovered from the glasstube walls after vaporization, for a percent yield of 73.3%.

Example 80

Ketorolac ethyl ester (MW 283, oral dose 10 mg), an analgesic, wascoated on an aluminum foil substrate (20 cm²) according to Method C.9.20 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 4.6 μm. The substrate was heated as described inMethod C at 60 V for 12 seconds. The purity of the drug-aerosolparticles was determined to be 99%. 5.19 mg was recovered from the glasstube walls after vaporization, for a percent yield of 56.4%.

Example 81

Ketorolac methyl ester (MW 269, oral dose 10 mg) was also coated on analuminum foil substrate (20 cm²) to a drug film thickness of 2.4 μm (4.8mg drug applied). The substrate was heated as described in Method C at60 V for 6 seconds. The purity of the drug-aerosol particles wasdetermined to be 98.8%. 3.17 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 66.0%.

Example 82

Ketotifen (MW 309, melting point 152° C., used as 0.025% solution in theeye) was coated on a stainless steel cylinder (8 cm²) according toMethod D. 0.544 mg of drug was applied to the substrate, for acalculated drug film thickness of 0.7 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.9%. 0.435 mg wasrecovered from the filter after vaporization, for a percent yield of80%. A total mass of 0.544 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 83

Lamotrigine (MW 256, melting point 218° C., oral dose 150 mg), ananticonvulsant, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.93 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.1%. 0.58 mg wasrecovered from the filter after vaporization, for a percent yield of62.4%. A total mass of 0.93 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 84

Lidocaine (MW 234, melting point 69° C., oral dose 30 mg), ananesthetic, was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 9.50 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 4.8 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 99.8%. 7.3 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of76.8%.

Lidocaine was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 10.4 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 4.24 μm. The substratewas heated as described in Method G at 90 V for 6 seconds. The purity ofthe drug-aerosol particles was determined to be >99%. 10.2 mg of thedrug was found to have aerosolized, for a percent yield of 98%.

Example 85

Linezolid (MW 337, melting point 183° C., oral dose 600 mg), ananti-infective agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.09 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.3 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 95%. 0.70 mg wasrecovered from the filter after vaporization, for a percent yield of64.2%. A total mass of 1.09 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 86

Loperamide (MW 477, oral dose 4 mg), a gastrointestinal agent, wascoated on a stainless steel cylinder (9 cm²) according to Method D. 1.57mg of drug was applied to the substrate, for a calculated drug filmthickness of 1.8 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 99.4%. 0.871 mg was recovered from thefilter after vaporization, for a percent yield of 55.5%. A total mass of1.57 mg was recovered from the test apparatus and substrate, for a totalrecovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by80 milliseconds. Generation of the thermal vapor was complete by 165milliseconds.

Example 87

Loratadine (MW 383, melting point 136° C., oral dose 10 mg), anantihistamine, was coated on an aluminum foil substrate (20 cm²)according to Method C. 5.80 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.9 μm. The substrate washeated as described in Method C at 60 V for 9 seconds. The purity of thedrug-aerosol particles was determined to be 99%. 3.5 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of60.3%.

Another substrate containing loratadine coated (6.60 mg drug) to a filmthickness of 3.3 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 9 seconds. The purity of the drug-aerosolparticles was determined to be 99.6%. 4.5 mg was recovered from theglass tube walls after vaporization, for a percent yield of 68.2%.

Loratadine was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 10.4 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 4.24 μm. The substratewas heated substantially as described in Method G at 90 V for 6 seconds,except that two of the openings of the T-shaped tube were left open andthe third connected to the 1 L flask. The purity of the drug-aerosolparticles was determined to be >99%. 3.8 mg of the drug was found tohave aerosolized, for a percent yield of 36.5%.

Example 88

Lovastatin (MW 405, melting point 175° C., oral dose 20 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.71 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 94.1%. 0.43 mg wasrecovered from the filter after vaporization, for a percent yield of60.6%. A total mass of 0.63 mg was recovered from the test apparatus andsubstrate, for a total recovery of 88.7%.

Example 89

Lorazepam N,O-diacetyl (typical inhalation dose 0.5 mg), was coated on apiece of aluminum foil (20 cm²) according to Method C. The calculatedthickness of the drug film was 0.5 μm. The substrate was heated asdescribed in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 90%. 0.87 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of87%.

Example 90

Loxapine (MW 328, melting point 110° C., oral dose 30 mg), apsychotherapeutic agent, was coated on a stainless steel cylinder (8cm²) according to Method D. 7.69 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 9.2 μm. The substratewas heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 99.7%.3.82 mg was recovered from the filter after vaporization, for a percentyield of 50%. A total mass of 6.89 mg was recovered from the testapparatus and substrate, for a total recovery of 89.6%.

Example 91

Maprotiline (MW 277, melting point 94° C., oral dose 25 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.0 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.0 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 99.7%. 1.3 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 65.0%.

Another substrate containing maprotiline coated to a film thickness of1.0 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 99.6%. 1.5 mg was recovered from theglass tube walls after vaporization, for a percent yield of 75%.

Example 92

Meclizine (MW 391, melting point <25° C., oral dose 25 mg), a vertigoagent, was coated on an aluminum foil substrate (20 cm²) according toMethod C. 5.20 mg of drug was applied to the substrate, for a calculatedthickness of the drug film of 2.6 μm. The substrate was heated asdescribed in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 90.1%. 3.1 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of59.6%.

The same drug coated on an identical substrate (aluminum foil (20 cm²))to a calculated drug film thickness of 12.5 μm was heated under an argonatmosphere as described in Method C at 60 V for 10 seconds. The purityof the drug-aerosol particles was determined to be 97.3%. 4.81 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 19.2%.

The dihydrochloride salt form of the drug was also tested. Meclizinedihydrochloride (MW 464, oral dose 25 mg) was coated on a piece ofaluminum foil (20 cm²) according to Method C. 19.4 mg of drug wasapplied to the substrate, for a calculated thickness of the drug film of9.7 μm. The substrate was heated as described in Method C at 60 V for 6seconds. The purity of the drug-aerosol particles was determined to be75.3%. 0.5 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 2.6%.

An identical substrate having a calculated drug film thickness of 11.7μm was heated under an argon atmosphere at 60 V for 6 seconds. Purity ofthe drug-aerosol particles was determined to be 70.9%. 0.4 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 1.7%.

Example 93

Memantine (MW 179, melting point <25° C., oral dose 20 mg), anantiparkinsonian agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. The calculated thickness of the drug film was 1.7μm. The substrate was heated as described in Method D by charging thecapacitors to 20.5 V. The purity of the drug-aerosol particlesdetermined by LC/MS was >99.5%. 0.008 mg was recovered from the glasstube walls after vaporization, for a percent yield of 0.6%. The totalmass recovered was 0.06 mg, for a total recovery yield of 4.5%. Theamount of drug trapped on the filter was low, most of the aerosolparticles escaped into the vacuum line.

Example 94

Meperidine (MW 247, oral dose 50 mg), an analgesic, was coated on analuminum foil substrate (20 cm²) according to Method C. 1.8 mg of drugwas applied to the substrate, for a calculated thickness of the drugfilm of 0.9 μm. The substrate was heated as described in Method C at 90V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be 98.8%. 0.95 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 52.8%.

Another substrate containing meperidine coated to a film thickness of1.1 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 99.9%. 1.02 mg was recovered from theglass tube walls after vaporization, for a percent yield of 48.6%.

Example 95

Metaproterenol (MW 211, melting point 100° C., oral dose 1.3 mg), arespiratory agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.35 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.6 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.1%. 0.81 mg wasrecovered from the filter after vaporization, for a percent yield of60%. A total mass of 1.2 mg was recovered from the test apparatus andsubstrate, for a total recovery of 88.9%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by150 milliseconds. Generation of the thermal vapor was complete by 300milliseconds.

Example 96

Methadone (MW 309, melting point 78° C., oral dose 2.5 mg), ananalgesic, was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 1.80 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 0.9 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 92.3%. 1.53 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 85%.

Example 97

Methoxsalen (MW 216, melting point 148° C., oral dose 35 mg), a skin andmucous membrane agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.03 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.2 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.6%. 0.77 mg wasrecovered from the filter after vaporization, for a percent yield of74.8%. A total mass of 1.03 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by80 milliseconds. Generation of the thermal vapor was complete by 135milliseconds.

Example 98

Metoprolol (MW 267, oral dose 15 mg), a cardiovascular agent, was coatedon an aluminum foil substrate (20 cm²) according to Method C. 10.8 mg ofdrug was applied to the substrate, for a calculated thickness of thedrug film of 5.4 μm. The substrate was heated as described in Method Cat 90 V for 5 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.2%. 6.7 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 62.0%.

Metoprolol was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 12.7 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 5.18 μm. The substratewas heated as described in Method G at 90 V for 6 seconds. The purity ofthe drug-aerosol particles was determined to be >99%. All of the drugwas found to have aerosolized, for a percent yield of 100%.

Example 99

Mexiletine HCl (MW 216, melting point 205° C., oral dose 200 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.75 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.4%. 0.44 mg wasrecovered from the filter after vaporization, for a percent yield of58.7%. A total mass of 0.75 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by75 milliseconds. Generation of the thermal vapor was complete by 200milliseconds.

Example 100

Midazolam (MW 326, melting point 160° C., oral dose 2.5 mg), a sedativeand hypnotic, was coated onto five stainless steel cylindricalsubstrates according to Method E. The calculated thickness of the drugfilm on each substrate ranged from about 1.1 μm to about 5.8 μm. Thesubstrates were heated as described in Method E and purity of thedrug-aerosol particles determined. The results are shown in FIG. 12.

Another substrate (stainless steel cylindrical, 6 cm²) was prepared bydepositing 5.37 mg drug to obtain a drug film thickness of 9 μm. Aftervolatilization of drug from this substrate according to Method E, 3.11mg was recovered from the filter, for a percent yield of 57.9%. A totalmass of 5.06 mg was recovered from the test apparatus and substrate, fora total recovery of 94.2%. Purity of the drug aerosol particles was99.5%. The yield of aerosol particles was 57.9%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by130 milliseconds. Generation of the thermal vapor was complete by 240milliseconds.

Midazolam was also coated on an aluminum foil substrate (28.8 cm²)according to Method C. 5.0 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 1.74 μm. The substratewas heated substantially as described in Method C at 60 V for 6 seconds.The purity of the drug-aerosol particles was determined to be 99.9%.

Another aluminum foil substrate (36 cm²) was prepared essentiallyaccording to Method G. 16.7 mg of midazolam was applied to thesubstrate, for a calculated thickness of the drug film of 4.64 μm. Thesubstrate was heated substantially as described in Method G at 90 V for6 seconds, except that one of the openings of the T-shaped tube wassealed with a rubber stopper, one was loosely covered with the end ofthe halogen tube, and the third connected to the 1 L flask. The purityof the drug-aerosol particles was determined to be >99%. All of the drugwas found to have aerosolized, for a percent yield of 100%.

Example 101

Mirtazapine (MW 265, melting point 116° C., oral dose 10 mg), apsychotherapeutic agent used as an antidepressant, was coated on analuminum foil substrate (24.5 cm²) according to Method G. 20.7 mg ofdrug was applied to the substrate, for a calculated thickness of thedrug film of 8.4 μm. The substrate was heated as described in Method Gat 90 V for 6 seconds. The purity of the drug-aerosol particles wasdetermined to be 99%. 10.65 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 51.4%.

Example 102

Morphine (MW 285, melting point 197° C., oral dose 15 mg), an analgesic,was coated on a stainless steel cylinder (8 cm²) according to Method D.2.33 mg of drug was applied to the substrate, for a calculated drug filmthickness of 2.8 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 99.1%. 1.44 mg was recovered from thefilter after vaporization, for a percent yield of 61.8%. A total mass of2.2 mg was recovered from the test apparatus and substrate, for a totalrecovery of 94.2%.

Morphine (MW 285, melting point 197° C., oral dose 15 mg), an analgesic,was coated on a piece of aluminum foil (20 cm²) according to Method C.The calculated thickness of the drug film was 4.8 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 92.5%. 3.1 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of32.3%.

Example 103

Nalbuphine (MW 357, melting point 231° C., oral dose 10 mg), ananalgesic, was coated onto four stainless steel cylinder substrates (8cm²) according to Method D. The calculated thickness of the drug film oneach substrate ranged from about 0.7 μm to about 2.5 μm. The substrateswere heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles from each substrate wasdetermined and the results are shown in FIG. 13. For the substratehaving a drug film thickness of 0.7 μm, 0.715 mg of drug was applied tothe substrate. After volatilization of this substrate, 0.455 mg wasrecovered from the filter, for a percent yield of 63.6%. A total mass of0.715 mg was recovered from the test apparatus and substrate, for atotal recovery of 100%.

Example 104

Naloxone (MW 327, melting point 184° C., oral dose 0.4 mg), an antidote,was coated on an aluminum foil (20 cm²) according to Method C. 2.10 mgof drug was applied to the substrate, for a calculated thickness of thedrug film of 1.1 μm. The substrate was heated as described in Method Cat 90 V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be 78.4%. 1.02 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 48.6%.

Another substrate containing naloxone coated to a film thickness of 1.0μm was prepared by the same method and heated under an argon atmosphereat 90 V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.2%. 1.07 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 53.5%.

Example 105

Naproxen (MW 230, melting point 154° C., oral dose 200 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. 8.7 mg were coated on the foil for a calculated thickness ofthe drug film of 4.4 μm. The substrate was heated as described in MethodC at 60 V for 7 seconds. The purity of the drug-aerosol particles wasdetermined to be >99.5%. 4.4 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 50.5%.

Example 106

Naratriptan (MW 335, melting point 171° C., oral dose 1 mg), a migrainepreparation, was coated onto seven stainless steel cylinder substrates(8 cm²) according to Method D. The calculated thickness of the drug filmon each substrate ranged from about 0.5 μm to about 2.5 μm. Thesubstrates were heated as described in Method D by charging thecapacitors to 20.5 V. Purity of the drug-aerosol particles from eachsubstrate was determined and the results are shown in FIG. 14. For thesubstrate having a drug film thickness of 0.6 μm, 0.464 mg of drug wasapplied to the substrate. After vaporization of this substrate bycharging the capacitors to 20.5 V. 0.268 mg was recovered from thefilter, for a percent yield of 57.8%. The purity was determined to be98.7%. A total mass of 0.464 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by100 milliseconds. Generation of the thermal vapor was complete by 250milliseconds.

Example 107

Nefazodone (MW 470, melting point 84° C., oral dose 75 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 4.6μm. The substrate was heated as described in Method C at 60 V for 15seconds. The purity of the drug-aerosol particles was determined to be91%. 4.4 mg was recovered from the glass tube walls after vaporization,for a percent yield of 47.8%.

Another substrate containing nefazodone coated to a film thickness of3.2 μm was prepared by the same method and heated under an argonatmosphere at 60 V for 15 seconds. The purity of the drug-aerosolparticles was determined to be 97.5%. 4.3 mg was recovered from theglass tube walls after vaporization, for a percent yield of 68.3%.

Example 108

Nortriptyline (MW 263, oral dose 15 mg), a psychotherapeutic agent, wascoated on an aluminum foil substrate (20 cm²) according to Method C. Thecalculated thickness of the drug film was 1.0 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 99.1%. 1.4 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 70.0%.

Another substrate containing nortriptyline was prepared for testingunder an argon atmosphere. 1.90 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.0 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 97.8%. 1.6 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 84.2%.

Example 109

Olanzapine (MW 312, melting point 195° C., oral dose 10 mg), apsychotherapeutic agent, was coated onto eight stainless steel cylindersubstrates (8-9 cm²) according to Method D. The calculated thickness ofthe drug film on each substrate ranged from about 1.2 μm to about 7.1μm. The substrates were heated as described in Method D by charging thecapacitors to 20.5 V. Purity of the drug-aerosol particles from eachsubstrate was determined and the results are shown in FIG. 15. Thesubstrate having a thickness of 3.4 μm was prepared by depositing 2.9 mgof drug. After volatilization of drug from this substrate by chargingthe capacitors to 20.5 V, 1.633 mg was recovered from the filter, for apercent yield of 54.6%. The purity of the drug aerosol recovered fromthe filter was found to be 99.8%. The total mass was recovered from thetest apparatus and substrate, for a total recovery of ˜100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by80 milliseconds. Generation of the thermal vapor was complete by 130milliseconds.

Olanzapine was also coated on an aluminum foil substrate (24.5 cm²)according to Method G. 11.3 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 4.61 μm. The substrate washeated as described in Method G at 90 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be >99%. 7.1 mg was collectedfor a percent yield of 62.8%.

Example 110

Orphenadrine (MW 269, melting point <25° C., oral dose 60 mg), a musclerelaxant, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 1.0 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 seconds.The purity of the drug-aerosol particles was determined to be >99.5%.1.35 mg was recovered from the glass tube walls after vaporization, fora percent yield of 71.1%.

Example 111

Oxycodone (MW 315, melting point 220° C., oral dose 5 mg), an analgesic,was coated on an aluminum foil substrate (20 cm²) according to Method C.2.4 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 1.2 μm. The substrate was heated as described inMethod C at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 99.9%. 1.27 mg was recovered from theglass tube walls after vaporization, for a percent yield of 52.9%.

Example 112

Oxybutynin (MW 358, oral dose 5 mg), a urinary tract agent, was coatedon a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 2.8 μm. The substrate washeated as described in Method C at 60 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be 90.6%. 3.01 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of54.7%.

Example 113

Parecoxib (MW 370, oral dose 10 mg), a non-steroidal anti-inflammatoryanalgesic, was coated on a piece of stainless steel foil (5 cm²)according to Method B. The calculated thickness of the drug film was 6.0μm. The substrate was heated as described in Method B by charging thecapacitors to 15.5 V. The purity of the drug-aerosol particles wasdetermined to be 80%. 1.264 mg was recovered from the filter aftervaporization, for a percent yield of 39.5%.

Another substrate (stainless steel foil, 5 cm²) was prepared by applying0.399 mg drug to form a film having a thickness of 0.8 μm. The substratewas heated as described in Method B by charging the capacitors to 15 V.The purity of the drug-aerosol particles was determined to be 97.2%.0.323 mg was recovered from the filter after vaporization, for a percentyield of 81.0%. A total mass of 0.324 mg was recovered from the testapparatus and substrate, for a total recovery of 81.3%.

Example 114

Paroxetine (MW 329, oral dose 20 mg), a psychotherapeutic agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 2.02mg of drug was applied to the substrate, for a calculated drug filmthickness of 2.4 μm. The substrate was heated as described in Method D(with the single exception that the circuit capacitance was 1.5 Farad,not 2.0 Farad), and purity of the drug-aerosol particles was determinedto be 99.5%. 1.18 mg was recovered from the filter after vaporization,for a percent yield of 58.4%. A total mass of 1.872 mg was recoveredfrom the test apparatus and substrate, for a total recovery of 92.7%.

Paroxetine was also coated on an aluminum foil substrate (24.5 cm²) asdescribed in Method G. 19.6 mg of drug was applied to the substrate, fora calculated drug film thickness of 8 μm. The substrate was heated asdescribed in Method G at 90 V for 6 seconds purity of the drug-aerosolparticles was determined to be 88%. 7.4 mg were lost from the substrateafter vaporization, for a percent yield of 37.8%.

Example 115

Pergolide (MW 314, melting point 209° C., oral dose 1 mg), anantiparkinsonian agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.43 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.7%. 1.18 mg wasrecovered from the filter after vaporization, for a percent yield of82.5%. A total mass of 1.428 mg was recovered from the test apparatusand substrate, for a total recovery of 99.9%.

Pergolide was also coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 1.2 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 seconds.The purity of the drug-aerosol particles was determined to be 98%. 0.52mg was recovered from the glass tube walls after vaporization, for apercent yield of 22.6%.

High speed photographs were taken as the drug-coated substrate accordingto Method D was heated to monitor visually formation of a thermal vapor.The photographs showed that a thermal vapor was initially visible 30milliseconds after heating was initiated, with the majority of thethermal vapor formed by 225 milliseconds. Generation of the thermalvapor was complete by 800 milliseconds.

Pergolide was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 1.0 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 0.4 μm. The substrate washeated substantially as described in Method G at 90 V for 6 seconds,except that two of the openings of the T-shaped tube were left open andthe third connected to the 1 L flask. The purity of the drug-aerosolparticles was determined to be >99%. All of the drug was found to haveaerosolized via weight loss from the substrate, for a percent yield of100%.

Example 116

Phenytoin (MW 252, melting point 298° C., oral dose 300 mg), ananticonvulsant, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.9 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be >99.5%. 0.6 mg wasrecovered from the filter after vaporization, for a percent yield of66.7%. A total mass of 0.84 mg was recovered from the test apparatus andsubstrate, for a total recovery of 93.3%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. Thephotographs, shown in FIGS. 24A-24D, showed that a thermal vapor wasinitially visible 25 milliseconds after heating was initiated, with themajority of the thermal vapor formed by 90 milliseconds. Generation ofthe thermal vapor was complete by 225 milliseconds.

Example 117

Pindolol (MW 248, melting point 173° C., oral dose 5 mg), acardiovascular agent, was coated on an aluminum foil substrate (20 cm²)according to Method C. 4.7 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.4 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be >99.5%. 2.77 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 58.9%.

Another substrate containing pindolol coated to a film thickness of 3.3μm was prepared by the same method and heated under an argon atmosphereat 60 V for 7 seconds. The purity of the drug-aerosol particles wasdetermined to be >99.5%. 3.35 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 50.8%.

Example 118

Pioglitazone (MW 356, melting point 184° C., oral dose 15 mg), anantidiabetic agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.48 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.6 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 95.6%. 0.30 mg wasrecovered from the filter after vaporization, for a percent yield of62.5%. A total mass of 0.37 mg was recovered from the test apparatus andsubstrate, for a total recovery of 77.1%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by100 milliseconds. Generation of the thermal vapor was complete by 125milliseconds.

Example 119

Piribedil (MW 298, melting point 98° C., IV dose 3 mg), anantiparkinsonian agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.1 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.5 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.7%. 1.01 mg wasrecovered from the filter after vaporization, for a percent yield of91.8%. A total mass of 1.1 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 120

Pramipexole (MW 211, oral dose 0.5 mg), an antiparkinsonian agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 1.05mg of drug was applied to the substrate, for a calculated drug filmthickness of 1.4 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 99.3%. 0.949 mg was recovered from thefilter after vaporization, for a percent yield of 90.4%. A total mass of1.05 mg was recovered from the test apparatus and substrate, for a totalrecovery of 100%.

Pramipexole was also coated on a piece of stainless steel foil (5 cm²)according to Method B. 0.42 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method B by charging the capacitors to 14 V. The purity ofthe drug-aerosol particles was determined to be 98.9%. 0.419 mg wasrecovered from the filter after vaporization, for a percent yield of99.8%. A total mass of 0.42 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by80 milliseconds. Generation of the thermal vapor was complete by 140milliseconds.

Example 121

Procainamide (MW 236, oral dose 125 mg), a cardiovascular agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 0.95mg of drug was applied to the substrate, for a calculated drug filmthickness of 1.1 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be >99.5%. 0.56 mg was recovered from thefilter after vaporization, for a percent yield of 58.9%. A total mass of0.77 mg was recovered from the test apparatus and substrate, for a totalrecovery of 81.1%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by90 milliseconds. Generation of the thermal vapor was complete by 250milliseconds.

Example 122

Prochlorperazine free base (MW 374, melting point 60° C., oral dose 5mg), a psychotherapeutic agent, was coated onto four stainless steelfoil substrates (5 cm²) according to Method B. The calculated thicknessof the drug film on each substrate ranged from about 2.3 μm to about10.1 μm The substrates were heated as described in Method B by chargingthe capacitors to 15 V. Purity of the drug-aerosol particles from eachsubstrate was determined and the results are shown in FIG. 18.

Prochlorperazine, a psychotherapeutic agent, was also coated on astainless steel cylinder (8 cm²) according to Method D. 1.031 mg of drugwas applied to the substrate, for a calculated drug film thickness of1.0 μm. The substrate was heated as described in Method D by chargingthe capacitors to 19 V. The purity of the drug-aerosol particles wasdetermined to be 98.7%. 0.592 mg was recovered from the filter aftervaporization, for a percent yield of 57.4%. A total mass of 1.031 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Example 123

Promazine (MW 284, melting point <25° C., oral dose 25 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 5.3μm. The substrate was heated as described in Method C at 90 V for 5seconds. The purity of the drug-aerosol particles was determined to be94%. 10.45 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 99.5%.

Example 124

Promethazine (MW 284, melting point 60° C., oral dose 12.5 mg), agastrointestinal agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 5.10 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 2.6 μm. Thesubstrate was heated as described in Method C at 60 V for 10 seconds.The purity of the drug-aerosol particles was determined to be 94.5%. 4.7mg was recovered from the glass tube walls after vaporization, for apercent yield of 92.2%.

Example 125

Propafenone (MW 341, oral dose 150 mg), a cardiovascular agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 0.77mg of drug was applied to the substrate, for a calculated drug filmthickness of 0.9 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be >99.5%. 0.51 mg was recovered from thefilter after vaporization, for a percent yield of 66.2%. A total mass of0.77 mg was recovered from the test apparatus and substrate, for a totalrecovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 20 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by60 milliseconds. Generation of the thermal vapor was complete by 110milliseconds.

Example 126

Propranolol (MW 259, melting point 96° C., oral dose 40 mg), acardiovascular agent, was coated on an aluminum foil substrate (20 cm²)according to Method C. 10.30 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 5.2 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 99.6%. 8.93 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of86.7%.

Example 127

Quetiapine (MW 384, oral dose 75 mg), a psychotherapeutic agent, wascoated onto eight stainless steel cylinder substrates (8 cm²) accordingto Method D. The calculated thickness of the drug film on each substrateranged from about 0.1 μm to about 7.1 μm. The substrates were heated asdescribed in Method D by charging the capacitors to 20.5 V. Purity ofthe drug-aerosol particles from each substrate was determined and theresults are shown in FIG. 16. The substrate having a drug film thicknessof 1.8 μm was prepared by depositing 1.46 mg drug. After volatilizationof drug this substrate by charging the capacitors to 20.5 V. 0.81 mg wasrecovered from the filter, for a percent yield of 55.5%. The purity ofthe drug aerosol recovered from the filter was found to be 99.1%. Atotal mass of 1.24 mg was recovered from the test apparatus andsubstrate, for a total recovery of 84.9%.

Example 128

Quinidine (MW 324, melting point 175° C., oral dose 100 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.51 mg of drug was applied to the substrate, fora calculated drug film thickness of 1.8 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be >99.5%. 0.88 mg wasrecovered from the filter after vaporization, for a percent yield of58.3%. A total mass of 1.24 mg was recovered from the test apparatus andsubstrate, for a total recovery of 82.1%.

Example 129

Rizatriptan (MW 269, melting point 121° C., oral dose 5 mg), a migrainepreparation, was coated on a stainless steel cylinder (6 cm²) accordingto Method E. 2.1 mg of drug was applied to the substrate, for acalculated drug film thickness of 3.5 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 99.2%. 1.66 mg was recovered from the filter aftervaporization, for a percent yield of 79%. A total mass of 2.1 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Rizatriptan was further coated on an aluminum foil substrate (150 cm²)according to Method F. 10.4 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 0.7 μm. The substrate washeated as described in Method F at 250° C. and the purity of thedrug-aerosol particles was determined to be 99%. 1.9 mg was collected inglass wool for a percent yield of 18.3%.

Another aluminum foil substrate (36 cm²) was prepared according toMethod G. 11.6 mg of rizatriptan was applied to the substrate, for acalculated thickness of the drug film of 3.2 μm. The substrate washeated substantially as described in Method G at 90 V for 7 seconds,except that one of the openings of the T-shaped tube was sealed with arubber stopper, one was loosely covered with the end of the halogentube, and the third connected to the 1 L flask. The purity of thedrug-aerosol particles was determined to be >99%. All of the drug wasfound to have aerosolized, for a percent yield of 100%.

Example 130

Rofecoxib (MW 314, oral dose 50 mg), an analgesic, was coated on analuminum foil substrate (20 cm²) according to Method C. 6.5 mg of drugwas applied to the substrate, for a calculated thickness of the drugfilm of 3.3 μm. The substrate was heated as described in Method C at 60V for 17 seconds. The purity of the drug-aerosol particles wasdetermined to be 97.5%. 4.1 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 63.1%.

Example 131

Ropinirole (MW 260, oral dose 0.25 mg), an antiparkinsonian agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D.0.754 mg of drug was applied to the substrate, for a calculated drugfilm thickness of 1.0 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 99%. 0.654 mg was recoveredfrom the filter after vaporization, for a percent yield of 86.7%. Atotal mass of 0.728 mg was recovered from the test apparatus andsubstrate, for a total recovery of 96.6%.

Example 132

Sertraline (MW 306, oral dose 25 mg), a psychotherapeutic agent used asan antidepressant (Zoloft®), was coated on a stainless steel cylinder (6cm²) according to Method E. 3.85 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 6.4 μm. The substratewas heated as described in Method E and purity of the drug-aerosolparticles was determined to be 99.5%. 2.74 mg was recovered from thefilter after vaporization, for a percent yield of 71.2%.

Sertraline was also coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 3.3μm. The substrate was heated as described in Method C at 60 V for 10seconds. The purity of the drug-aerosol particles was determined to be98.0%. 5.35 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 81.1%.

Another sertraline coated substrate (aluminum foil, 20 cm²) having adrug film thickness of 0.9 μm was heated as described in Method C undera pure argon atmosphere at 90 V for 3.5 seconds. The purity of thedrug-aerosol particles was determined to be 98.7%. 1.29 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of75.9%.

High speed photographs were taken as the drug-coated substrate fromMethod D was heated to monitor visually formation of a thermal vapor.The photographs showed that a thermal vapor was initially visible 30milliseconds after heating was initiated, with the majority of thethermal vapor formed by 135 milliseconds. Generation of the thermalvapor was complete by 250 milliseconds.

Example 133

Selegiline (MW 187, melting point <25° C., oral dose 5 mg), anantiparkinsonian agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 3.7 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.9 μm. The substrate washeated as described in Method C at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 99.2%. 2.41 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of65.1%.

Example 134

Sildenafil (MW 475, melting point 189° C., oral dose 25 mg), an agentused for erectile dysfunction (Viagra®)), was coated onto six stainlesssteel foil substrates (5 cm²) according to Method B. The calculatedthickness of the drug film on each substrate ranged from about 0.5 μm toabout 1.6 μm. The substrates were heated as described in Method B bycharging the capacitors to 16 V. Purity of the drug-aerosol particlesfrom each substrate was determined and the results are shown in FIG. 22.

Sildenafil was also coated on a stainless steel cylinder (6 cm²)according to Method E. 1.9 mg of drug was applied to the substrate, fora calculated drug film thickness of 3.2 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 81%. 1.22 mg was recovered from the filter aftervaporization, for a percent yield of 64.2%. A total mass of 1.5 mg wasrecovered from the test apparatus and substrate, for a total recovery of78.6%.

Sildenafil was also coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 2.5μm. The substrate was heated as described in Method C at 90 V for 4seconds. The purity of the drug-aerosol particles was determined to be66.3%. 1.05 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 21%.

Sildenafil was also coated on a piece of stainless steel foil (6 cm²)according to Method B. 0.227 mg of drug was applied to the substrate,for a calculated drug film thickness of 0.4 μm. The substrate was heatedas described in Method B by charging the capacitors to 16 V. The purityof the drug-aerosol particles was determined to be 99.3%. 0.224 mg wasrecovered from the filter after vaporization, for a percent yield of98.7%. A total mass of 0.227 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 45 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by250 milliseconds. Generation of the thermal vapor was complete by 400milliseconds.

Sildenafil was also coated on a piece of aluminum foil at a calculatedfilm thickness of 3.4 μm, 3.3 μm, 1.6 μm, 0.8 μm, 0.78 μm, 0.36 μm, 0.34μm, 0.29 μm, and 0.1 μm. The coated substrate was placed on an aluminumblock that was preheated to 275° C. using a hot plate. A Pyrex® beakerwas synchronously placed over the foil and the substrate was heated for1 minute. The material collected on the beaker walls was recovered andanalyzed by reverse-phase HPLC analysis with detection by absorption of250 nm light to determine the purity of the aerosol. The purity of thedrug-aerosol particles was determined to be 84.8% purity at 3.4 μmthickness; 80.1% purity at 3.3 μm thickness; 89.8% purity at 1.6 μmthickness; 93.8% purity at 0.8 μm thickness; 91.6% purity at 0.78 μmthickness; 98.0% purity at 0.36 μm thickness; 98.6% purity at 0.34 μmthickness; 97.6% purity at 0.29 μm thickness; and 100% purity at 0.1 μmthickness.

Example 135

Spironolactone (MW 417, melting point 135° C., oral dose 25 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.71 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be >99.5%. 0.41 mg wasrecovered from the filter after vaporization, for a percent yield of57.7%. A total mass of 0.7 mg was recovered from the test apparatus andsubstrate, for a total recovery of 98.6%.

Example 136

Sumatriptan (MW 295, melting point 171° C., oral dose 6 mg), a migrainepreparation, was coated on a stainless steel cylinder (8 cm²) accordingto Method E. 1.22 mg of drug was applied to the substrate, for acalculated drug film thickness of 1.5 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 97.9%. 0.613 mg was recovered from the filter aftervaporization, for a percent yield of 50.2%. A total mass of 1.03 mg wasrecovered from the test apparatus and substrate, for a total recovery of84.4%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by175 milliseconds. Generation of the thermal vapor was complete by 600milliseconds.

Example 137

Sibutramine (MW 280, oral dose 10 mg), an obesity management appetitesuppressant, was coated on a stainless steel cylinder (8 cm²) accordingto Method D. 1.667 mg of drug was applied to the substrate, for acalculated drug film thickness of 2 μm. The substrate was heated asdescribed in Method D (with the single exception that the circuitcapacitance was 1.5 Farad, not 2.0 Farad), and purity of thedrug-aerosol particles was determined to be 94%. 0.861 mg was recoveredfrom the filter after vaporization, for a percent yield of 51.6%. Atotal mass of 1.35 mg was recovered from the test apparatus andsubstrate, for a total recovery of 81%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by55 milliseconds. Generation of the thermal vapor was complete by 150milliseconds.

Example 138

Tamoxifen (MW 372, melting point 98° C., oral dose 10 mg), anantineoplastic, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.46 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.6 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 91.4%. 0.27 mg wasrecovered from the filter after vaporization, for a percent yield of58.7%. A total mass of 0.39 mg was recovered from the test apparatus andsubstrate, for a total recovery of 84.8%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by70 milliseconds. Generation of the thermal vapor was complete by 250milliseconds.

Example 139

Tacrine (MW 198, melting point 184° C.), an Alzheimer's disease manager,was coated on a stainless steel cylinder (8 cm²) according to Method D.0.978 mg of drug was applied to the substrate, for a calculated drugfilm thickness of 1.2 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 99.8%. 0.502 mg wasrecovered from the filter after vaporization, for a percent yield of51.3%. A total mass of 0.841 mg was recovered from the test apparatusand substrate, for a total recovery of 86%.

Example 140

Tadalafil (MW 389, oral dose 5 mg), an erectile dysfunction therapeuticagent, was coated onto eight stainless steel foil substrates (5 cm²)according to Method B. The calculated thickness of the drug film on eachsubstrate ranged from about 0.5 μm to about 2.9 μm. The substrates wereheated as described in Method B by charging the capacitors to 16 V.Purity of the drug-aerosol particles from each substrate was determinedand the results are shown in FIG. 17.

Tadalafil was also coated on a stainless steel cylinder (8 cm²). Thecalculated thickness of the drug film was 4.5 μm. The substrate washeated as described by the flashbulb and the purity of the drug-aerosolparticles was determined to be 94.9%. 0.67 mg was recovered from thefilter after vaporization, for a percent yield of 18.1%. A total mass of1.38 mg was recovered from the test apparatus and substrate, for a totalrecovery of 37.3%.

Tadalafil was also coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 0.5 μm. Thesubstrate was heated as described in Method C at 60 V for 13 seconds.The purity of the drug-aerosol particles was determined to be 91.2%.0.45 mg was recovered from the glass tube walls after vaporization, fora percent yield of 45%.

Tadalafil was also coated on a piece of stainless steel foil (5 cm²)according to Method B. 1.559 mg of drug was applied to the substrate,for a calculated drug film thickness of 2.9 μm. The substrate was heatedas described in Method B by charging the capacitors to 16 V. The purityof the drug-aerosol particles was determined to be 95.8%. 1.42 mg wasrecovered from the filter after vaporization, for a percent yield of91.1%. A total mass of 1.559 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

The drug was also coated (1.653 mg) to a thickness of 3.1 μm on a pieceof stainless steel foil (5 cm²) according to Method B. The substrate washeated under an N₂ atmosphere by charging the capacitors to 16 V. Thepurity of the drug-aerosol particles was determined to be 99.2%. 1.473mg was recovered from the filter after vaporization, for a percent yieldof 89.1%. A total mass of 1.653 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

Example 141

Terbutaline (MW 225, melting point 122° C., oral dose 0.2 mg), arespiratory agent, was coated on a stainless steel cylinder (9 cm²)according to Method D. 2.32 mg of drug was applied to the substrate, fora calculated drug film thickness of 2.7 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.3%. 1.54 mg wasrecovered from the filter after vaporization, for a percent yield of66.4%. A total mass of 1.938 mg was recovered from the test apparatusand substrate, for a total recovery of 83.5%.

Example 142

Testosterone (MW 288, melting point 155° C., oral dose 3 mg), a hormone,was coated on a stainless steel cylinder (8 cm²) according to Method D.0.96 mg of drug was applied to the substrate, for a calculated drug filmthickness of 1.2 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 99.6%. 0.62 mg was recovered from thefilter after vaporization, for a percent yield of 64.6%. A total mass of0.96 mg was recovered from the test apparatus and substrate, for a totalrecovery of 100%.

Example 143

Thalidomide (MW 258, melting point 271° C., oral dose 100 mg), animmunomodulator, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.57 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.7 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be >99.5%. 0.43 mg wasrecovered from the filter after vaporization, for a percent yield of75.4%. A total mass of 0.54 mg was recovered from the test apparatus andsubstrate, for a total recovery of 94.7%.

Example 144

Theophylline (MW 180, melting point 274° C., oral dose 200 mg), arespiratory agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.859 mg of drug was applied to the substrate,for a calculated drug film thickness of 1.0 μm. The substrate was heatedas described in Method D by charging the capacitors to 20.5 V. Thepurity of the drug-aerosol particles was determined to be 100.0%. 0.528mg was recovered from the filter after vaporization, for a percent yieldof 61.5%. A total mass of 0.859 mg was recovered from the test apparatusand substrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 40 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by160 milliseconds. Generation of the thermal vapor was complete by 350milliseconds.

Example 145

Tocainide (MW 192, melting point 247° C., oral dose 400 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.86 mg of drug was applied to the substrate, fora calculated drug film thickness of 1 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.7%. 0.65 mg wasrecovered from the filter after vaporization, for a percent yield of75.6%. A total mass of 0.86 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by75 milliseconds. Generation of the thermal vapor was complete by 130milliseconds.

Example 146

Tolfenamic Acid (MW 262, melting point 208° C., oral dose 200 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 5.0 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 94.2%. 6.49 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 65.6%.

Example 147

Tolterodine (MW 325, oral dose 2 mg), an urinary tract agent, was coatedon a stainless steel cylinder (8 cm²) according to Method D. 1.39 mg ofdrug was applied to the substrate, for a calculated drug film thicknessof 1.7 μm. The substrate was heated as described in Method D by chargingthe capacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 96.9%. 1.03 mg was recovered from the filter aftervaporization, for a percent yield of 74.1%. A total mass of 1.39 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by80 milliseconds. Generation of the thermal vapor was complete by 100milliseconds.

Example 148

Toremifene (MW 406, melting point 110° C., oral dose 60 mg), anantineoplastic, was coated on a stainless steel cylinder (8 cm²). 1.20mg of drug was applied to the substrate, for a calculated thickness ofthe drug film of 1.4 μm, and heated to form drug-aerosol particlesaccording to Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 98.7%. The yield ofaerosol particles was 50%. 1.09 mg of total mass was recovered for atotal recovery yield of 90.8%.

Example 149

Tramadol (MW 263, oral dose 50 mg), an analgesic, was coated on analuminum foil substrate (20 cm²) according to Method C. 4.90 mg of drugwas applied to the substrate, for a calculated thickness of the drugfilm of 2.5 μm. The substrate was heated as described in Method C at 108V for 2.25 seconds. The purity of the drug-aerosol particles wasdetermined to be 96.9%. 3.39 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 69.2%.

Tramadol (2.6 mg) was also coated on a piece of aluminum foil (20 cm²)according to Method C to a film thickness (calculated) of 1.3 μm. Thesubstrate was heated as described in Method C under an argon atmosphereat 90 V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be 96.1%. 1.79 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 68.8%.

Tramadol (2.1 mg) was also coated on a piece of aluminum foil (20 cm²)according to Method C to a film thickness (calculated) of 1.1 μm. Thesubstrate was heated as described in Method C under air at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be96.6%. 1.33 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 63.8%.

The hydrochloride salt form was also tested. 2.6 mg of drug was coatedonto an aluminum foil substrate (20 cm²) according to Method C to a filmthickness (calculated) of 1.3 μm. The substrate was heated as describedin Method C and purity of the drug-aerosol particles was determined tobe 97.6%. 1.67 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 64.2%. An identical substratehaving an identical drug film thickness was tested under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 89%. 1.58 mg was recovered from the glasstube walls after vaporization, for a percent yield of 60.8%

Tramadol (17.5 mg) was also coated on a piece of aluminum foil (40 cm²)according to Method F to a film thickness (calculated) of 4.38 μm. Thesubstrate was heated as described in Method F and purity of thedrug-aerosol particles was determined to be 97.3%.

Example 150

Tranylcypromine (MW 133, melting point <25° C., oral dose 30 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 5.4μm. The substrate was heated as described in Method C at 90 V for 5seconds. The purity of the drug-aerosol particles was determined to be93.7%. 7.4 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 68.5%.

Another substrate containing tranylcypromine coated to a film thicknessof 2.7 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 95.9%. 3 mg was recovered from the glasstube walls after vaporization, for a percent yield of 56.6%.

Tranylcypromine HCl (MW 169, melting point 166° C., oral dose 30 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.2μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be97.5%. 1.3 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 56.5%.

Example 151

Trazodone (MW 372, melting point 87° C., oral dose 400 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 10.0 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 5.0 μm. Thesubstrate was heated as described in Method C at 60 V for 15 seconds.The purity of the drug-aerosol particles was determined to be 98.9%. 8.5mg was recovered from the glass tube walls after vaporization, for apercent yield of 85%.

Trazodone was further coated on an aluminum foil substrate according toMethod G. The substrate was heated as described in Method G at 90 V for3.5 seconds. The purity of the drug-aerosol particles was determined tobe 97.9%. The percent yield of the aerosol was 29.1%. The purity of thedrug-aerosol particles was determined to be 98.5% when the system wasflushed through with argon prior to volatilization. The percent yield ofthe aerosol was 25.5%.

Example 152

Triazolam (MW 343, melting point 235° C., oral dose 0.13 mg), a sedativeand hypnotic, was coated on an aluminum foil substrate (20 cm²)according to Method C. 1.7 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 0.9 μm. The substrate washeated as described in Method C at 45 V for 18 seconds. The purity ofthe drug-aerosol particles was determined to be 99.2%. 1.6 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 94.1%.

Another aluminum foil substrate (28.8 cm²) was prepared according toMethod C. 1.7 mg of triazolam was applied to the substrate, for acalculated thickness of the drug film of 0.69 μm. The substrate washeated substantially as described in Method C at 75 V for 2 seconds andthen at 45 V for 8 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.3%. 1.7 mg of aerosol particles were collected for apercent yield of 100%.

Triazolam was also applied to an aluminum foil substrate (36 cm²)according to Method G. 0.6 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 0.17 μm. The substratewas heated substantially as described in Method G at 90 V for 6 seconds,except that one of the openings of the T-shaped tube was sealed with arubber stopper, one was loosely covered with the end of the halogentube, and the third connected to the 1 L flask. The purity of thedrug-aerosol particles was determined to be >99%. All of the drug wasfound to have aerosolized, for a percent yield of 100%.

Example 153

Trifluoperazine (MW 407, melting point <25° C., oral dose 7.5 mg), apsychotherapeutic agent, was coated on a stainless steel cylinder (9cm²) according to Method D. 1.034 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 1.1 μm. The substratewas heated as described in Method D by charging the capacitors to 19 V.The purity of the drug-aerosol particles was determined to be 99.8%.0.669 mg was recovered from the filter after vaporization, for a percentyield of 64.7%. A total mass of 1.034 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

Trifluoperazine 2HCl salt (MW 480, melting point 243° C., oral dose 7.5mg) was coated on an identical substrate. Specifically, 0.967 mg of drugwas applied to the substrate, for a calculated drug film thickness of1.1 μm. The substrate was heated as described in Method D by chargingthe capacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 87.5%. 0.519 mg was recovered from the filter aftervaporization, for a percent yield of 53.7%. A total mass of 0.935 mg wasrecovered from the test apparatus and substrate, for a total recovery of96.7%.

High speed photographs of trifluoperazine 2HCl were taken as thedrug-coated substrate was heated to monitor visually formation of athermal vapor. The photographs showed that a thermal vapor was initiallyvisible 25 milliseconds after heating was initiated, with the majorityof the thermal vapor formed by 120 milliseconds. Generation of thethermal vapor was complete by 250 milliseconds.

Example 154

Trimipramine maleate (MW 411, melting point 142° C., oral dose 50 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.2μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be95.9%. 1.6 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 66.7%.

Another substrate containing trimipramine maleate coated to a filmthickness of 1.1 μm was prepared by the same method and heated under anargon atmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 97.4%. 2.1 mg was recovered from theglass tube walls after vaporization, for a percent yield of 95.5%.

Example 155

Valdecoxib (MW 314, melting point 155° C., oral dose 10 mg), anantirheumatic agent, was coated on a piece of stainless steel foil (5cm²) according to Method B. The calculated thickness of the drug filmwas 8.0 μm. The substrate was heated as described in Method B bycharging the capacitors to 15.5 V. The purity of the drug-aerosolparticles was determined to be 96.9%. 1.235 mg was recovered from thefilter after vaporization, for a percent yield of 28.9%. A total mass of3.758 mg was recovered from the test apparatus and substrate, for atotal recovery of 87.9%.

Valdecoxib was also coated on a piece of stainless steel foil (6 cm²)according to Method B. 0.716 mg of drug was applied to the substrate,for a calculated drug film thickness of 1.3 μm. The substrate was heatedas described in Method B by charging the capacitors to 15 V. The purityof the drug-aerosol particles was determined to be 98.6%. 0.466 mg wasrecovered from the filter after vaporization, for a percent yield of65.1%. A total mass of 0.49 mg was recovered from the test apparatus andsubstrate, for a total recovery of 68.4%.

Example 156

Valproic Acid (MW 144, melting point <25° C., oral dose 60 mg), ananticonvulsant, was coated on a metal substrate (50 cm²) according toMethod F. 82.4 mg of drug was applied to the substrate, for a calculateddrug film thickness of 16.5 μm. The substrate was heated according toMethod F at 300° C. to form drug-aerosol particles. Purity of thedrug-aerosol particles was determined to be 99.7% by GC analysis. 60 mgof the drug were collected for a percent yield of 72.8%.

Example 157

Vardenafil (MW 489, oral dose 5 mg), an erectile dysfunction therapyagent, was coated on a stainless steel cylinder (6 cm²) according toMethod E. The calculated thickness of the drug film was 2.7 μm. Thesubstrate was heated as described in Method E and purity of thedrug-aerosol particles was determined to be 79%. 0.723 mg was recoveredfrom the filter after vaporization, for a percent yield of 44.4%.

Another substrate (stainless steel cylinder (6 cm²)) was prepared byapplying 0.18 mg drug to form a film 0.3 μm in thickness. The substratewas heated as described in Method E and purity of the drug-aerosolparticles was determined to be 96.8%. 0.11 mg was recovered from thefilter after vaporization, for a percent yield of 63.1%. A total mass of0.14 mg was recovered from the test apparatus and substrate, for a totalrecovery of 81.8%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by90 milliseconds. Generation of the thermal vapor was complete by 110milliseconds.

Example 158

Venlafaxine (MW 277, oral dose 50 mg), a psychotherapeutic agent, wascoated on a stainless steel cylinder (6 cm²) according to Method E. 5.85mg of drug was applied to the substrate, for a calculated drug filmthickness of 9.8 μm. The substrate was heated as described in Method Eand purity of the drug-aerosol particles was determined to be 99.4%.3.402 mg was recovered from the filter after vaporization, for a percentyield of 58.1%. A total mass of 5.85 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by100 milliseconds. Generation of the thermal vapor was complete by 400milliseconds.

Example 159

Verapamil (MW 455, melting point <25° C., oral dose 40 mg), acardiovascular agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated under an argon atmosphere at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be96.2%. 1.41 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 64.1%.

Verapamil was also coated on a stainless steel cylinder (8 cm²)according to Method D. 0.75 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 89.6%. 0.32 mg wasrecovered from the filter after vaporization, for a percent yield of42.7%. A total mass of 0.6 mg was recovered from the test apparatus andsubstrate, for a total recovery of 80%.

Example 160

Vitamin E (MW 430, melting point 4° C.), a dietary supplement, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 0.78mg of drug was applied to the substrate, for a calculated drug filmthickness of 0.9 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 99.3%. 0.48 mg was recovered from thefilter after vaporization, for a percent yield of 61.8%. A total mass of0.6 mg was recovered from the test apparatus and substrate, for a totalrecovery of 81.4%.

Example 161

Zaleplon (MW 305, melting point 159° C., oral dose 5 mg), a sedative andhypnotic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 2.3 μm. Thesubstrate was heated as described in Method C at 60 V for 12 seconds.The purity of the drug-aerosol particles was determined to be 99.5%.4.07 mg was recovered from the glass tube walls after vaporization, fora percent yield of 90.4%.

Example 162

Zolmitriptan (MW 287, melting point 141° C., oral dose 1.25 mg), amigraine preparation, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.6μm. The substrate was heated as described in Method C at 60 V for 11seconds. The purity of the drug-aerosol particles was determined to be93%. 1.1 mg was recovered from the glass tube walls after vaporization,for a percent yield of 35.5%.

Another substrate containing zolmitriptan coated to a film thickness of2.0 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 4 seconds. The purity of the drug-aerosolparticles was determined to be 98.4%. 0.6 mg was recovered from theglass tube walls after vaporization, for a percent yield of 15%.

Another substrate (36 cm²) containing zolmitriptan was preparedaccording to Method C. 9.8 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 2.7 μm. The substrate washeated substantially as described in Method C at 60 V for 15 seconds.The purity of the drug-aerosol particles was determined to be 98%. Theaerosol percent yield was 38%.

Zolmitriptan was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 2.6 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 1.1 μm. The substrate washeated as described in Method G at 90 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be >96%. 1.5 mg of the drug wasfound to have aerosolized, for a percent yield of 57.7%.

Example 163

Zolpidem (MW 307, melting point 196° C., oral dose 5 mg), a sedative andhypnotic, was coated onto six stainless steel cylindrical substratesaccording to Method E. The calculated thickness of the drug film on eachsubstrate ranged from about 0.1 μm to about 4.2 μm. The substrates wereheated as described in Method E and purity of the drug-aerosol particlesgenerated from each substrate determined. The results are shown in FIG.19.

Zolpidem was also coated on a stainless steel cylinder (6 cm²) accordingto Method E. 4.13 mg of drug was applied to the substrate, for acalculated drug film thickness of 6.9 μm. The substrate was heated asdescribed in Method E and purity of the drug-aerosol particles wasdetermined to be 96.6%. 2.6 mg was recovered from the filter aftervaporization, for a percent yield of 63%. A total mass of 3.18 mg wasrecovered from the test apparatus and substrate, for a total recovery of77%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 35 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by120 milliseconds. Generation of the thermal vapor was complete by 225milliseconds.

Zolpidem was also coated on an aluminum substrate (24.5 cm²) accordingto Method G. 8.3 mg of drug was applied to the substrate, for acalculated drug film thickness of 3.4 μm. The substrate was heated asdescribed in Method G at 90 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be >97%. 7.4 mg of the drug wasfound to have aerosolized by weight loss from substrate mass, for apercent yield of 89.2%.

Example 164

Zopiclone (MW 388, melting point 178° C., oral dose 7.50 mg), a sedativeand hypnotic, was coated on an aluminum foil substrate (20 cm²)according to Method C. 3.7 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.9 μm. The substrate washeated as described in Method C at 60 V for 9 seconds. The purity of thedrug-aerosol particles was determined to be 97.9%. 2.5 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of67.6%.

Zopiclone was further coated on an aluminum foil substrate (24 cm²)according to Method C. 3.5 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 1.5 μm. The substrate washeated substantially as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be >99%.

Example 165

Zotepine (MW 332, melting point 91° C., oral dose 25 mg), apsychotherapeutic agent, was coated on a stainless steel cylinder (8cm²) according to Method D. 0.82 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 1 μm. The substratewas heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 98.3%.0.72 mg was recovered from the filter after vaporization, for a percentyield of 87.8%. A total mass of 0.82 mg was recovered from the testapparatus and substrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by60 milliseconds. Generation of the thermal vapor was complete by 110milliseconds.

Example 166

Adenosine (MW 267, melting point 235° C., oral dose 6 mg), ananti-arrhythmic cardiovascular agent, was coated on a stainless steelcylinder (8 cm²) according to Method D. 1.23 mg of drug was applied tothe substrate, for a calculated drug film thickness of 1.5 μm. Thesubstrate was heated as described in Method D by charging the capacitorsto 20.5 V. The purity of the drug-aerosol particles was determined to be70.6%. 0.34 mg was recovered from the filter after vaporization, for apercent yield of 27.6%. A total mass of 0.68 mg was recovered from thetest apparatus and substrate, for a total recovery of 55.3%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 40 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by250 milliseconds. Generation of the thermal vapor was complete by 535milliseconds.

Example 167

Amoxapine (MW 314, melting point 176° C., oral dose 25 mg), ananti-psychotic agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 6.61 mg of drug was applied to the substrate, fora calculated drug film thickness of 7.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 99.7%. 3.13 mg wasrecovered from the filter after vaporization, for a percent yield of47.4%. A total mass of 6.61 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

Example 168

Apomorphine 10,11 cyclocarbonate (MW 293, typical aerosol dose 1 mg), adopaminergic agent used in Parkinson's patients, was coated on a pieceof aluminum foil (20 cm²) according to Method C. The calculatedthickness of the drug film was 1.2 μm. The substrate was heated asdescribed in Method C at 90 V for 3 seconds. The purity of thedrug-aerosol particles was determined to be 78.4%. 1.46 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of60.8%.

Example 169

Aripiprazole (MW 448, melting point 140° C., oral dose 5 mg), ananti-psychotic agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 1.139 mg of drug was applied to the substrate,for a calculated drug film thickness of 1.4 μm. The substrate was heatedas described in Method D by charging the capacitors to 20.5 V. Thepurity of the drug-aerosol particles was determined to be 91.1%. 0.251mg was recovered from the filter after vaporization, for a percent yieldof 22%. A total mass of 1.12 mg was recovered from the test apparatusand substrate, for a total recovery of 98%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 55 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by300 milliseconds. Generation of the thermal vapor was complete by 1250milliseconds.

A second substrate coated with arirpirazole was prepared for testing.1.139 mg was coated on a stainless steel cylinder (8 cm²) according toMethod D, for a calculated drug film thickness of 1.4 μm. The substratewas heated as described in Method D by charging the capacitors to 20.5V. The purity of the drug-aerosol particles was determined to be 86.9%.0.635 mg was recovered from the filter after vaporization, for a percentyield of 55.8%. A total mass of 1.092 mg was recovered from the testapparatus and substrate, for a total recovery of 95.8%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by200 milliseconds. Generation of the thermal vapor was complete by 425milliseconds.

Example 170

Aspirin (MW 180, melting point 135° C., oral dose 325 mg), an analgesicagent, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 1.2 μm. Thesubstrate was heated as described in Method C at 60 V for 5 seconds. Thepurity of the drug-aerosol particles was determined to be 82.1%. 1.23 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 53.5%.

Example 171

Astemizole (MW 459, melting point 173° C., oral dose 10 mg), anantihistamine, was coated on an aluminum foil substrate (20 cm²)according to Method C. 5.0 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.5 μm. The substrate washeated as described in Method C at 60 V for 11 seconds. The purity ofthe drug-aerosol particles was determined to be 88%. 1.6 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 32.0%.

A similarly prepared substrate having the same film thickness was heatedat 60 V for 11 seconds under a pure argon atmosphere. The purity of thedrug-aerosol particles was determined to be 93.9%. 1.7 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of34.0%.

Example 172

Atenolol (MW 266, melting point 152° C., oral dose 25 mg), a betaadrenergic blocking agent, was coated on a piece of aluminum foil (20cm²) according to Method C. 22.6 mg was applied to the substrate, for acalculated thickness of the drug film of 11.3 μm. The substrate washeated as described in Method C at 60 V for 11 seconds. The purity ofthe drug-aerosol particles was determined to be 94%. 1.0 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 4.4%.

Another atenolol-coated substrate was prepared by the same method, with17.9 mg of drug applied to the substrate, for a calculated filmthickness of 9.0 μm. The substrate was heated under an argon atmosphereaccording to Method C at 60 V for 3.5 seconds. The purity of thedrug-aerosol particles was determined to be >99.5%. 2.0 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of11%.

Atenolol was further coated on an aluminum foil substrate according toMethod G. The substrate was heated as described in Method G, and thepurity of the drug-aerosol particles was determined to be 100%. Thepercent yield of the aerosol was 10%.

Example 173

Benazepril (MW 424, melting point 149° C., oral dose 10 mg), an ACEinhibitor, cardiovascular agent, was coated on a stainless steelcylinder (8 cm²) according to Method D. The calculated thickness of thedrug film was 0.9 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 90%. 0.34 mg was recovered from thefilter after vaporization, for a percent yield of 45.3%. A total mass of0.6 mg was recovered from the test apparatus and substrate, for a totalrecovery of 77.3%.

Example 174

Benztropine (MW 307, melting point 143° C., oral dose 1 mg), ananti-cholinergic, antiparkinsonian agent, was coated onto an aluminumfoil substrate (20 cm²) according to Method C. 2.10 mg of drug wasapplied to the substrate, for a calculated thickness of the drug film of1.1 μm. The substrate was heated as described in Method C at 90 V for3.5 seconds. The purity of the drug-aerosol particles was determined tobe 98.3%. 0.83 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 39.5%.

Another benztropine-coated substrate was prepared by the same method,with 2.0 mg of drug was applied to the substrate, for a calculated filmthickness of 1.0 μm. The substrate was heated under an argon atmosphereat 90 V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be 99.5%. 0.96 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 48%.

Example 175

Bromazepam (MW 316, melting point 239° C., oral dose 2 mg), apsychotherapeutic agent used as an anti-anxiety drug, was coated on apiece of aluminum foil (20 cm²) according to Method C. The calculatedthickness of the drug film was 5.2 μm. The substrate was heated asdescribed in Method C at 30 V for 45 seconds. The purity of thedrug-aerosol particles was determined to be 96.9%. 2.2 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of21.2%.

Example 176

Budesonide (MW 431, melting point 232° C., oral dose 0.2 mg), ananti-inflammatory steroid used as a respiratory agent, was coated on astainless steel cylinder (9 cm²) according to Method D. 1.46 mg of drugwas applied to the substrate, for a calculated drug film thickness of1.7 μm. The substrate was heated as described in Method D by chargingthe capacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 70.5%. 0.37 mg was recovered from the filter aftervaporization, for a percent yield of 25.3%. A total mass of 0.602 mg wasrecovered from the test apparatus and substrate, for a total recovery of41.2%.

Example 177

Buspirone (MW 386, oral dose 15 mg), a psychotherapeutic agent, wascoated on an aluminum foil substrate (20 cm²) according to Method C.7.60 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 3.8 μm. The substrate was heated as described inMethod C at 60 V for 7 seconds. The purity of the drug-aerosol particleswas determined to be 96.5%. 1.75 mg was recovered from the glass tubewalls after vaporization, for a percent yield of 23%.

Another substrate containing buspirone coated to a film thickness of 4.6μm was prepared by the same method and heated under an argon atmosphereat 60 V for 7 seconds. The purity of the drug-aerosol particles wasdetermined to be 96.1%. 2.7 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 29.7%.

The hydrochloride salt (MW 422) was also tested. Buspirone hydrochloridewas coated on a piece of aluminum foil (20 cm²) according to Method C.8.30 mg of drug was applied to the substrate, for a calculated thicknessof the drug film of 4.2 μm. The substrate was heated as described inMethod C at 90 V for 5 seconds. The purity of the drug-aerosol particleswas determined to be 97.8%. 2.42 mg was recovered from the glass tubewalls after vaporization, for a percent yield of 29.2%.

Example 178

Caffeine (MW 194, melting point 238° C., oral dose 100 mg), a centralnervous system stimulant, was coated on a metal substrate (50 cm²). 100mg of drug was applied to the substrate, for a calculated drug filmthickness of 14 μm and heated to 300° C. according to Method F to formdrug-aerosol particles. Purity of the drug-aerosol particles wasdetermined to be >99.5%. 40 mg was recovered from the glass wool aftervaporization, for a percent yield of 40%.

Example 179

Captopril (MW 217, melting point 104° C., oral dose 25 mg), an ACEinhibitor, cardiovascular agent, was coated on a stainless steelcylinder (8 cm²) according to Method D. 0.88 mg of drug was applied tothe substrate, for a calculated drug film thickness of 1.1 μm. Thesubstrate was heated as described in Method D by charging the capacitorsto 20.5 V. The purity of the drug-aerosol particles was determined to be87.5%. 0.54 mg was recovered from the filter after vaporization, for apercent yield of 61.4%. A total mass of 0.8 mg was recovered from thetest apparatus and substrate, for a total recovery of 90.9%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 20 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by100 milliseconds. Generation of the thermal vapor was complete by 170milliseconds.

Example 180

Carbamazepine (MW 236, melting point 193° C., oral dose 200 mg), ananticonvulsant agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.73 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.9 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 88.9%. 0.43 mg wasrecovered from the filter after vaporization, for a percent yield of58.9%. A total mass of 0.6 mg was recovered from the test apparatus andsubstrate, for a total recovery of 78.1%.

Example 181

Cinnarizine (MW 369, oral dose 15 mg), an antihistamine, was coated onan aluminum foil substrate (20 cm²) according to Method C. 18.0 mg ofdrug was applied to the substrate, for a calculated thickness of thedrug film of 9 μm. The substrate was heated as described in Method C at60 V for 8 seconds. The purity of the drug-aerosol particles wasdetermined to be 96.7%. 3.15 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 17.5%.

Another substrate containing cinnarizine coated (5.20 mg drug) to a filmthickness of 2.6 μm was prepared by the same method and heated under anargon atmosphere at 60 V for 8 seconds. The purity of the drug-aerosolparticles was determined to be 91.8%. 2.3 mg was recovered from theglass tube walls after vaporization, for a percent yield of 44.2%.

Example 182

Clemastine (MW 344, melting point <25° C., oral dose 1 mg), aantihistamine, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 3.2 μm. Thesubstrate was heated as described in Method C at 60 V for 7 seconds. Thepurity of the drug-aerosol particles was determined to be 94.3%. 3 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 46.9%.

Clemastine fumarate (MW 460, melting point 178° C., oral dose 1.34 mg)was coated on an identical substrate to a thickness of 2.9 μm. Thesubstrate was heated at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 76.6%. 1.8 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of31.6%.

Example 183

Clofazimine (MW 473, melting point 212° C., oral dose 100 mg), ananti-infective agent, was coated on a stainless steel cylinder (6 cm²)according to Method D. 0.48 mg of drug was applied to the substrate, fora calculated drug film thickness of 0.8 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 84.4%. 0.06 mg wasrecovered from the filter after vaporization, for a percent yield of12.5%. A total mass of 0.48 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 45 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by300 milliseconds. Generation of the thermal vapor was complete by 1200milliseconds.

Example 184

Desipramine (MW 266, melting point <25° C., oral dose 25 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 5.2μm. The substrate was heated as described in Method C at 90 V for 5seconds. The purity of the drug-aerosol particles was determined to be82.2%. 7.2 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 69.9%.

Example 185

Dipyridamole (MW 505, melting point 163° C., oral dose 75 mg), a bloodmodifier, was coated on a stainless steel cylinder (6 cm²) according toMethod D. 1.15 mg of drug was applied to the substrate, for a calculateddrug film thickness of 1.9 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 95.3%. 0.22 mg was recoveredfrom the filter after vaporization, for a percent yield of 19.1%. Atotal mass of 1.1 mg was recovered from the test apparatus andsubstrate, for a total recovery of 94.8%.

Example 186

Dolasetron (MW 324, oral dose 100 mg), a gastrointestinal agent, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 5 μm. The substrate was heatedas described in Method C at 30 V for 45 seconds. The purity of thedrug-aerosol particles was determined to be 83%. 6 mg was recovered fromthe glass tube walls after vaporization, for a percent yield of 60%.

Dolasetron was further coated on an aluminum foil substrate according toMethod C. The substrate was heated substantially as described in MethodC, and the purity of the drug-aerosol particles was determined to be99%.

Example 187

Doxylamine (MW 270, melting point <25° C., oral dose 12.5 mg), anantihistamine, was coated on a stainless steel cylinder (8 cm²)according to Method D. The calculated thickness of the drug film was 7.8μm. The substrate was heated as described in Method D by charging thecapacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 99.8%. 2.96 mg was recovered from the filter aftervaporization, for a percent yield of 45.6%. A total mass of 6.49 mg wasrecovered from the test apparatus and substrate, for a total recovery of100%.

Example 188

Droperidol (MW 379, melting point 147° C., oral dose 1 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be51%. 0.27 mg was recovered from the glass tube walls after vaporization,for a percent yield of 12.9%.

Another substrate containing droperidol coated to a film thickness of1.0 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 65%. 0.24 mg was recovered from the glasstube walls after vaporization, for a percent yield of 12.6%.

Example 189

Enalapril maleate (MW 493, melting point 145° C., oral dose 5 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method D by charging thecapacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 61%. 0.29 mg was recovered from the filter aftervaporization, for a percent yield of 34.1%. A total mass of 0.71 mg wasrecovered from the test apparatus and substrate, for a total recovery of83.5%.

Example 190

Estradiol-17-acetate (MW 314, oral dose 2 mg), a hormonal pro-drug, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 0.9 μm. The substrate washeated as described in Method C at 60 V for 6 seconds. The purity of thedrug-aerosol particles was determined to be 98.6%. 0.59 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of34.7%.

Example 191

Estradiol 17-heptanoate (MW 384 melting point 94° C., oral dose 1 mg), ahormone, was coated on a metal substrate (50 cm²). 42 mg was applied tothe substrate, for a calculated drug film thickness of 8.4 μm and heatedaccording to Method F at 300° C. to form drug-aerosol particles. Purityof the drug-aerosol particles was determined to be 90% by GC analysis.The total mass recovered was 11.9%.

Example 192

Fluphenazine (MW 438, melting point <25° C., oral dose 1 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be93%. 0.7 mg was recovered from the glass tube walls after vaporization,for a percent yield of 33.3%.

The fluphenazine 2HCl salt form of the drug (MW 510, melting point 237°C.) was also tested. The drug was coated on a metal substrate (10 cm²)according to Method D. The calculated thickness of the drug film was 0.8μm. The substrate was heated as described in Method D by charging thecapacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 80.7%. 0.333 mg was recovered from the filter aftervaporization, for a percent yield of 42.6%. A total mass of 0.521 mg wasrecovered from the test apparatus and substrate, for a total recovery of66.7%.

Example 193

Flurazepam (MW 388, melting point 82° C., oral dose 15 mg), sedative andhypnotic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 2.5 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 99.2%. 1.8 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 36%.

Flurazepam was further coated on an aluminum foil substrate (24 cm²)according to Method C. 5 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 2.08 μm. The substratewas heated substantially as described in Method C at 60 V for 5 seconds.The purity of the drug-aerosol particles was determined to be 99.6%. Thepercent yield of the aerosol was 36%.

Example 194

Flurbiprofen (MW 244, melting point 111° C., oral dose 50 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 4.7 μm. Thesubstrate was heated as described in Method C at 60 V for 5 seconds. Thepurity of the drug-aerosol particles was determined to be >99.5%. 4.1 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 43.6%.

Example 195

Fluvoxamine (MW 318, oral dose 50 mg), a psychotherapeutic agent, wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 4.4 μm. The substrate washeated as described in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 65%. 6.5 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of77.8%.

Another substrate containing fluvoxamine coated to a film thickness of4.4 μm was prepared by the same method and heated under an argonatmosphere at 60 V for 8 seconds. The purity of the drug-aerosolparticles was determined to be 88%. 6.9 mg was recovered from the glasstube walls after vaporization, for a percent yield of 78.4%.

Example 196

Frovatriptan (MW 379, melting point 102° C., oral dose 2.5 mg), amigraine preparation, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 3.3μm. The substrate was heated as described in Method C at 60 V for 12seconds. The purity of the drug-aerosol particles was determined to be73%. 1.4 mg was recovered from the glass tube walls after vaporization,for a percent yield of 21.2%.

Frovatriptan was further coated on an aluminum foil substrate (24.5 cm²)according to Method G. 5.0 mg of the drug was applied to the substrate,for a calculated thickness of the drug film of 2.0 μm. The substrate washeated substantially as described in Method G at 90 V for 6 seconds,except that two of the openings of the T-shaped tube were left open andthe third connected to the 1 L flask. The purity of the drug-aerosolparticles was determined to be >91%. 2.8 mg of the drug was found tohave aerosolized by mass lost from substrate, for a percent yield of56%.

Example 197

Hydroxyzine (MW 375, oral dose 50 mg), an antihistamine, was coated on apiece of aluminum foil (20 cm²) according to Method C. The calculatedthickness of the drug film was 14 μm. The substrate was heated asdescribed in Method C at 60 V for 9 seconds. The purity of thedrug-aerosol particles was determined to be 93%. 5.54 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of19.9%.

The same drug coated on an identical substrate (aluminum foil, 20 cm²)to a calculated drug film thickness of 7.6 μm was heated under an argonatmosphere as described in Method C at 60 V for 9 seconds. Purity of thedrug-aerosol particles was determined to be 98.6%. 4.31 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of28.5%.

The dihydrochloride salt form of the drug was also tested. Hydroxyzinedihydrochloride (MW 448, melting point 193° C., oral dose 50 mg) wascoated on a piece of aluminum foil (20 cm²) according to Method C. Thecalculated thickness of the drug film was 13.7 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 41.2%. 0.25 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of0.9%.

The salt form of the drug coated on an identical substrate (aluminumfoil, 20 cm²) to a calculated drug film thickness of 12.8 μm was heatedunder an argon atmosphere as described in Method C at 60 V for 7seconds. Purity of the drug-aerosol particles was determined to be70.8%. 1.4 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 5.5%.

Example 198

Ibutilide was coated on a stainless steel cylinder (8 cm²) according toMethod D. 1.436 mg of drug was applied to the substrate, for acalculated drug film thickness of 1.7 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 98.4%. 0.555 mg wasrecovered from the filter after vaporization, for a percent yield of38.6%. A total mass of 1.374 mg was recovered from the test apparatusand substrate, for a total recovery of 95.7%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 25 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by300 milliseconds. Generation of the thermal vapor was complete by 1200milliseconds.

Example 199

Indomethacin norcholine ester (MW 429, oral dose 25 mg), an analgesic,was coated on a piece of aluminum foil (20 cm²) according to Method C.The calculated thickness of the drug film was 5.1 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be >99.5%. 2.94 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 29.1%.

Example 200

Ketorolac (MW 254, melting point 161° C., oral dose 10 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 1.1 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 65.7%. 0.73 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 33.2%.

Example 201

Ketorolac norcholine ester (MW 326, oral dose 10 mg), was coated on analuminum foil substrate (20 cm²) according to Method C. 2.70 mg of drugwas applied to the substrate, for a calculated thickness of the drugfilm of 1.4 μm. The substrate was heated as described in Method C at 60V for 5 seconds. The purity of the drug-aerosol particles was determinedto be 98.5%. 1.1 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 40.7%.

Example 202

Levodopa (MW 197, melting point 278° C., oral dose 500 mg), anantiparkinsonian agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 3.7μm. The substrate was heated as described in Method C at 45 V for 15seconds, then at 30 V for 10 seconds. The purity of the drug-aerosolparticles was determined to be 60.6%. The percent yield of the aerosolwas 7.2%.

Example 203

Melatonin (MW 232, melting point 118° C., oral dose 3 mg), a dietarysupplement, was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 2.0 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 1.0 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be >99.5%. 0.43 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 21.5%.

Another substrate containing melatonin coated to a film thickness of 1.1μm was prepared by the same method and heated under an argon atmosphereat 90 V for 3.5 seconds. The purity of the drug-aerosol particles wasdetermined to be >99.5%. 1.02 mg was recovered from the glass tube wallsafter vaporization, for a percent yield of 46.4%.

Example 204

Methotrexate (oral dose 2.5 mg) was coated on a stainless steel cylinder(8 cm²) according to Method D. The calculated thickness of the drug filmwas 1.3 μm. The substrate was heated as described in Method D bycharging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 66.3%. The percent yield of the aerosolwas 2.4%.

Example 205

Methysergide (MW 353, melting point 196° C., oral dose 2 mg), a migrainepreparation, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 1.0 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 seconds.The purity of the drug-aerosol particles was determined to be 67.5%.0.21 mg was recovered from the glass tube walls after vaporization, fora percent yield of 10.5%.

Example 206

Metoclopramide (MW 300, melting point 148° C., oral dose 10 mg), agastrointestinal agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.0 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.0 μm. The substrate washeated as under an argon atmosphere at 90 V for 3.5 seconds. The purityof the drug-aerosol particles was determined to be 99.1%. 0.43 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 21.7%.

Example 207

Nabumetone (MW 228, melting point 80° C., oral dose 1000 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 4.9 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be >99.5%. 4.8 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 49%.

Example 208

Naltrexone (MW 341, melting point 170° C., oral dose 25 mg), anantidote, was coated on an aluminum foil substrate (20 cm²) according toMethod C. 10.3 mg of drug was applied to the substrate, for a calculatedthickness of the drug film of 5.2 μm. The substrate was heated asdescribed in Method C at 90 V for 5 seconds. The purity of thedrug-aerosol particles was determined to be 96%. 3.3 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of32%.

Naltrexone was coated on an aluminum foil substrate (20 cm²) accordingto Method C. 1.8 mg of drug was applied to the substrate, for acalculated thickness of the drug film of 0.9 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds under an argonatmosphere. The purity of the drug-aerosol particles was determined tobe 97.4%. 1.0 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 55.6%.

Example 209

Nalmefene (MW 339, melting point 190° C., IV dose 0.5 mg), an antidote,was coated on a metal substrate (50 cm²). 7.90 mg of drug was coated onthe substrate, to form a calculated film thickness of 1.6 μm, and heatedaccording to Method F to form drug-aerosol particles. Purity of thedrug-aerosol particles was determined to be 80%. 2.7 mg was recoveredfrom the glass wool after vaporization, for a percent yield of 34%.

Example 210

Perphenazine (MW 404, melting point 100° C., oral dose 2 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.1 mg of drug was applied to the substrate,for a calculated thickness of the drug film of 1.1 μm. The substrate washeated as described in Method C at 90 V for 3.5 seconds. The purity ofthe drug-aerosol particles was determined to be 99.1%. 0.37 mg wasrecovered from the glass tube walls after vaporization, for a percentyield of 17.6%.

Example 211

Pimozide (MW 462, melting point 218° C., oral dose 10 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 4.9μm. The substrate was heated as described in Method C at 90 V for 5seconds. The purity of the drug-aerosol particles was determined to be79%. The percent yield of the aerosol was 6.5%.

Example 212

Piroxicam (MW 248, melting point 200° C., oral dose 20 mg), a CNS-activesteroid was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 5.0 μm. Thesubstrate was heated as described in Method C at 60 V for 7 seconds. Thepurity of the drug-aerosol particles was determined to be 87.7%. 2.74 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 27.7%.

Example 213

Pregnanolone (MW 318, melting point 150° C., typical inhalation dose 2mg), an anesthetic, was coated on a metal substrate (50 cm²). 20.75 mgwas coated on the substrate, for a calculated film thickness of 4.2 μm,and heated according to Method F at 300° C. to form drug-aerosolparticles. Purity of the drug-aerosol particles was determined to be87%. 9.96 mg of aerosol particles were collected for a percent yield of48%).

Example 214

Prochlorperazine 2HCl (MW 446, oral dose 5 mg), a psychotherapeuticagent, was coated on a stainless steel cylinder (8 cm²) according toMethod D. 0.653 mg of drug was applied to the substrate, for acalculated drug film thickness of 0.8 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 72.4%. 0.24 mg wasrecovered from the filter after vaporization, for a percent yield of36.8%. A total mass of 0.457 mg was recovered from the test apparatusand substrate, for a total recovery of 70%.

Example 215

Protriptyline HCl (MW 299, melting point 171° C., oral dose 15 mg), apsychotherapeutic agent, was coated on an aluminum foil substrate (20cm²) according to Method C. 2.20 mg of drug was applied to thesubstrate, for a calculated thickness of the drug film of 1.1 μm. Thesubstrate was heated as described in Method C at 90 V for 3.5 seconds.The purity of the drug-aerosol particles was determined to be 99.7%.0.99 mg was recovered from the glass tube walls after vaporization, fora percent yield of 45.0%.

Example 216

Protriptyline (MW 263, oral dose 15 mg) was coated on an aluminum foilsubstrate (20 cm²) according to Method C. 5.6 mg of drug was applied tothe substrate, for a calculated thickness of the drug film of 2.8 μm.The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be89.8%. 1.4 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 25%.

Another substrate containing protriptyline coated to a film thickness of2.7 μm was prepared by the same method and heated under an argonatmosphere at 90 V for 3.5 seconds. The purity of the drug-aerosolparticles was determined to be 90.8%. 1.4 mg was recovered from theglass tube walls after vaporization, for a percent yield of 26.4%.

Example 217

Pyrilamine (MW 285, melting point <25° C., oral dose 25 mg), anantihistamine, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 5.2 μm. Thesubstrate was heated as described in Method C at 60 V for 6 seconds. Thepurity of the drug-aerosol particles was determined to be 98.4%. 4.3 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 41.7%.

Pyrilamine maleate (MW 401, melting point 101° C., oral dose 25 mg), anantihistamine, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 10.8 μm. Thesubstrate was heated as described in Method C at 60 V for 7 seconds. Thepurity of the drug-aerosol particles was determined to be 93.7%. 10.5 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 48.8%.

Example 218

Quinine (MW 324, melting point 177° C., oral dose 260 mg), ananti-infective agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.1μm. The substrate was heated as described in Method C at 60 V for 6seconds. The purity of the drug-aerosol particles was determined tobe >99.5%. 0.9 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 40.9%.

Example 219

Ramipril (MW 417, melting point 109° C., oral dose 1.25 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)and heated to form drug-aerosol particles according to Method D bycharging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 61.5%. 0.27 mg was recovered from thefilter after vaporization, for a percent yield of 30%. A total mass of0.56 mg was recovered from the test apparatus and substrate, for a totalrecovery of 62.2%.

Example 220

Risperidone (MW 410, melting point 170° C., oral dose 2 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.4μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be79%. The percent yield of the aerosol was 7.9%.

Risperidone was also coated on a stainless steel cylinder (8 cm²). 0.75mg of drug was manually applied to the substrate, for a calculated drugfilm thickness of 0.9 μm. The substrate was heated as described inMethod D by charging the capacitors to 20.5 V. The purity of thedrug-aerosol particles was determined to be 87.3%. The percent yield ofaerosol particles was 36.7%. A total mass of 0.44 mg was recovered fromthe test apparatus and substrate, for a total recovery of 59.5%.

Example 221

Scopolamine (MW 303, melting point <25° C., oral dose 1.5 mg), agastrointestinal agent, was coated on a metal substrate (50 cm²)according to Method F at 200° C. 37.5 mg of drug was applied to thesubstrate, for a calculated drug film thickness of 7.5 μm. The substratewas heated according to Method F to form drug-aerosol particles. Purityof the drug-aerosol particles was determined to be 90% by GC analysis.1.2 mg were recovered for a percent yield of 3.2%.

Example 222

Sotalol (MW 272, oral dose 80 mg), a cardiovascular agent, was coated ona stainless steel cylinder (8 cm²) according to Method D. 1.8 mg of drugwas applied to the substrate, for a calculated drug film thickness of2.3 μm. The substrate was heated as described in Method D by chargingthe capacitors to 20.5 V. The purity of the drug-aerosol particles wasdetermined to be 96.9%. 0.66 mg was recovered from the filter aftervaporization, for a percent yield of 36.7%. A total mass of 1.06 mg wasrecovered from the test apparatus and substrate, for a total recovery of58.9%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 30 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by90 milliseconds. Generation of the thermal vapor was complete by 500milliseconds.

Example 223

Sulindac (MW 356, melting point 185° C., oral dose 150 mg), ananalgesic, was coated on a piece of aluminum foil (20 cm²) according toMethod C. The calculated thickness of the drug film was 4.3 μm. Thesubstrate was heated as described in Method C at 60 V for 8 seconds. Thepurity of the drug-aerosol particles was determined to be 80.4%. 1.19 mgwas recovered from the glass tube walls after vaporization, for apercent yield of 14%.

Example 224

Terfenadine (MW 472, melting point 149° C., oral dose 60 mg), anantihistamine, was coated on a piece of aluminum foil (20 cm²) accordingto Method C. The calculated thickness of the drug film was 2.5 μm. Thesubstrate was heated as described in Method C at 60 V for 8 seconds. Thepurity of the drug-aerosol particles was determined to be 75.4%. 0.178mg was recovered from the glass tube walls after vaporization, for apercent yield of 3.6%.

An identical substrate coated with terfenadine (2.8 μm thick) was heatedunder an argon atmosphere at 60 V for 8 seconds. The purity of thedrug-aerosol particles was determined to be 74.7%. 0.56 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of10.2%.

Example 225

Triamcinolone acetonide (MW 434, melting point 294° C., oral dose 0.2mg), a respiratory agent, was coated on a stainless steel cylinder (6cm²) according to Method D. 0.2 mg of drug was applied to the substrate,for a calculated drug film thickness of 0.3 μm. The substrate was heatedas described in Method D by charging the capacitors to 20.5 V. Thepurity of the drug-aerosol particles was determined to be 92%. 0.02 mgwas recovered from the filter after vaporization, for a percent yield of10%. A total mass of 0.09 mg was recovered from the test apparatus andsubstrate, for a total recovery of 45%.

Example 226

Trihexyphenidyl (MW 302, melting point 115° C., oral dose 2 mg), anantiparkinsonian agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 1.4μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be77%. 1.91 mg was recovered from the glass tube walls after vaporization,for a percent yield of 68.2%.

Example 227

Thiothixene (MW 444, melting point 149° C., oral dose 10 mg), apsychotherapeutic agent used as an anti-psychotic, was coated on a pieceof aluminum foil (20 cm²) according to Method C. The calculatedthickness of the drug film was 1.3 μm. The substrate was heated asdescribed in Method C at 90 V for 3.5 seconds. The purity of thedrug-aerosol particles was determined to be 74.0%. 1.25 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of48.1%.

Example 228

Telmisartan (MW 515, melting point 263° C., oral dose 40 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 2.73 mg of drug was applied to the substrate, fora calculated drug film thickness of 3.3 μm. The substrate was heated asdescribed in Method D by charging the capacitors to 20.5 V. The purityof the drug-aerosol particles was determined to be 96%. 0.64 mg wasrecovered from the filter after vaporization, for a percent yield of23.4%. A total mass of 2.73 mg was recovered from the test apparatus andsubstrate, for a total recovery of 100%.

High speed photographs were taken as the drug-coated substrate washeated to monitor visually formation of a thermal vapor. The photographsshowed that a thermal vapor was initially visible 50 milliseconds afterheating was initiated, with the majority of the thermal vapor formed by400 milliseconds. Generation of the thermal vapor was complete by 1100milliseconds.

Example 229

Temazepam (MW 301, melting point 121° C., oral dose 7.5 mg), a sedativeand hypnotic, was coated on an aluminum foil substrate (20 cm²)according to Method C. 4.50 mg of drug was applied to the substrate, fora calculated thickness of the drug film of 2.3 μm. The substrate washeated as described in Method C at 60 V for 7 seconds. The purity of thedrug-aerosol particles was determined to be 97.1%. 1.9 mg was recoveredfrom the glass tube walls after vaporization, for a percent yield of42.2%.

Example 230

Triamterene (MW 253, melting point 316° C., oral dose 100 mg), acardiovascular agent, was coated on a stainless steel cylinder (8 cm²)according to Method D. 0.733 mg of drug was applied to the substrate,for a calculated drug film thickness of was 0.9 μm. The substrate washeated as described in Method D by charging the capacitors to 20.5 V.The purity of the drug-aerosol particles was determined to be >99.5%.0.233 mg was recovered from the filter after vaporization, for a percentyield of 31.8%.

Example 231

Trimipramine (MW 294, melting point 45° C., oral dose 50 mg), apsychotherapeutic agent, was coated on a piece of aluminum foil (20 cm²)according to Method C. The calculated thickness of the drug film was 2.8μm. The substrate was heated as described in Method C at 90 V for 3.5seconds. The purity of the drug-aerosol particles was determined to be99.2%. 2.6 mg was recovered from the glass tube walls aftervaporization, for a percent yield of 46.4%.

Example 232

Ziprasidone (MW 413, oral dose 20 mg), an anti-psychotic agent, wascoated on a stainless steel cylinder (8 cm²) according to Method D. 0.74mg of drug was applied to the substrate, for a calculated drug filmthickness of 0.9 μm. The substrate was heated as described in Method Dby charging the capacitors to 20.5 V. The purity of the drug-aerosolparticles was determined to be 87.3%. 0.28 mg was recovered from thefilter after vaporization, for a percent yield of 37.8%. A total mass of0.44 mg was recovered from the test apparatus and substrate, for a totalrecovery of 59.5%.

Example 233

Zonisamide (MW 212, melting point 163° C., oral dose 75 mg), ananticonvulsant, was coated on a metal substrate and heated to formdrug-aerosol particles. The substrate was heated as described in MethodC and the purity of the drug-aerosol particles was determined to be99.7%. The percent yield of the aerosol was 38.3%.

Example 234 Preparation of Drug-Coated Stainless Steel Foil Substrate

Strips of clean 302/304 stainless-steel foil (0.0025 cm thick, ThinMetal Sales) having dimensions 1.5 cm by 7.0 cm were dip-coated with adrug solution. The final coated area was 5.1 cm by 1.5 cm on both sidesof the foil, for a total area of 15 cm². Foils were prepared as statedabove and then extracted with acetonitrile. The amount of drug wasdetermined from quantitative HPLC analysis. Using the known drug-coatedsurface area, the thickness was then obtained by:

film thickness(cm)=drug mass(g)/[drug density(g/cm³)×substratearea(cm²)]

If the drug density is not known, a value of 1 g/cm³ is assumed. Thefilm thickness in microns is obtained by multiplying the film thicknessin cm by 10,000. After drying, the drug-coated foil was placed into avolatilization chamber constructed of a Dekin® block (the airway) andbrass bars, which served as electrodes. The dimensions of the airwaywere 1.0 high by 5.1 wide by 15.2 cm long. The drug-coated foil wasplaced into the volatilization chamber such that the drug-coated sectionwas between the two sets of electrodes. After securing the top of thevolatilization chamber, the electrodes were connected to three 12Vbatteries wired in series with a switch controlled by circuit. Thecircuit was designed to close the switch in pulses so as to resistivelyheat the foil to a temperature within 50 milliseconds (typically between320° and 470° C.) and maintain that temperature for up to 3 seconds. Theback of the volatilization chamber was connected to a two micron Teflon®filter (Savillex) and filter housing, which were in turn connected tothe house vacuum. Sufficient airflow was initiated (typically 30.5L/min=1.0 m/sec). After the drug had vaporized, airflow was stopped andthe Teflon® filter was extracted with acetonitrile. Drug extracted fromthe filter was analyzed by HPLC UV absorbance at 225 nm using a gradientmethod aimed at detection of impurities to determine percent purity.Also, the extracted drug was quantified to determine a percent yield,based on the mass of drug initially coated onto the substrate. A percentrecovery was determined by quantifying any drug remaining on thesubstrate, adding this to the quantity of drug recovered in the filterand comparing it to the mass of drug initially coated onto thesubstrate.

Celecoxib and rizatriptan were tested together according to the methodabove, by coating a solution of the drug onto a piece of stainless steelfoil (15 cm²). Twelve substrates were prepared, with film thicknessesranging from about 4.4 μm to about 11.4 μm. The substrates were heatedas described in the method above to 350° C. Purity of the drug aerosolparticles from each substrate was determined. The substrate having athickness of 4.4 μm was prepared by depositing 0.98 mg of rizatriptanand 5.82 mg of celecoxib. After volatilization of drug this substrate,0.59 mg of rizatriptan and 4.40 mg of celecoxib were recovered from thefilter, for a percent yield of 73.6%. The purity of the aerosolparticles was 96.5%.

Example 235

Using a solution of 50 mg sildenafil+10 mg caffeine per mL of solvent(2:1 chloroform:methanol), 0.0025 cm thick stainless steel foils(dimensions of 5.0×6.9 cm) were coated with 4.1 mg of sildenafil and 0.5mg of caffeine on 45 cm² of surface area. After drying, a variation ofMethod B was used. However, instead of a capacitive discharge, afeedback circuit, powered by three 12 V sealed lead acid batteries inseries, was used to heat the foil to 425° C. and maintain thetemperature for 500 milliseconds. Also, the 1.3×2.6×8.9 cmairway/vaporization chamber of Method B was replaced with a 5.1 by 1.0by 15.3 cm airway to accommodate the larger foils. The airflow rate wasset at 30.5 L/m (1.0 m/s). The generated aerosol was captured in asingle Teflon filter, which was extracted with acetonitrile and analyzedon HPLC for purity and mass recovery. The purity of the aerosol was91.9% by peak area under the curve at 225 nm. The mass recovery in theextracted filter was 2.9 mg sildenafil and 0.5 mg caffeine.

Example 236

A number of other drugs were tested according to one of the abovemethods (A-G) or a similar method, but exhibited purity less than about60%. These drugs were not further tested for optimization: amiloride,amiodarone, amoxicillin, beclomethasone, bromocriptine, bufexamac,candesartan, candesartan cilexetil, cetirizine, cortisone, cromolyn,cyclosporin A, dexamethasone, diclofenac, dihydroergotamine, disulfiram,dofetilide, edrophonium chloride, famotidine, fexofenadine, formoterol,furosemide, heparin, ipratropium bromide, irbesartan, labetalol,lansoprazole, lisuride, lorazepam, losartan, methocarbamol, metolazone,modafinil, montelukast, myricetin, nadolol, omeprazole, ondansetron,oxazepam, phenelzine, phentermine, propantheline bromide, quinaprilhydrochloride, rabeprazole, raloxifene, rosiglitazone, tolmetin,torsemide, valsartan, and zafirlukast.

Example 237 General Procedure for Determining Whether a Drug is a “HeatStable Drug”

Drug is dissolved or suspended in a solvent (e.g., dichloromethane ormethanol). The solution or suspension is coated to about a 4 micronthickness on a stainless steel substrate of about 8 cm² surface area.The substrate may either be a standard stainless steel foil or aheat-passivated stainless steel foil. The substrate is heated to atemperature sufficient to generate a thermal vapor (generally ˜350° C.)but at least to a temperature of 200° C. with an air flow typically of20 L/min (1 m/s) passing over the film during heating. The heating isdone in a volatilization chamber fitted with a trap (such as describedin the Examples above). After vaporization is complete, airflow isdiscontinued and the resultant aerosol is analyzed for purity using themethods disclosed herein. If the resultant aerosol contains less than10% drug degradation product, i.e., the TSR≧9, then the drug is a heatstable drug. If, however, at about 4 micron thickness, greater than 10%degradation is determined, the experiment is repeated at the sameconditions, except that film thicknesses of about 1.5 microns, and ofabout 0.5 micron, respectively, are used. If a decrease in degradationproducts relative to the 4 micron thickness is seen at either of thesethinner film thicknesses, a plot of film thickness versus purity isgraphed and extrapolated out to a film thickness of 0.05 microns. Thegraph is used to determine if there exists a film thickness where thepurity of the aerosol would be such that it contains less than 10% drugdegradation products. If such a point exists on the graph, then the drugis defined as a heat stable drug.

Example 238 General Procedure for Screening Drugs to DetermineAerosolization Preferability

Drug (1 mg) is dissolved or suspended in a minimal amount of solvent(e.g., dichloromethane or methanol). The solution or suspension ispipeted onto the middle portion of a 3 cm by 3 cm piece of aluminumfoil. The coated foil is wrapped around the end of a 1½ cm diameter vialand secured with parafilm. A hot plate is preheated to approximately300° C., and the vial is placed on it foil side down. The vial is lefton the hotplate for 10 s after volatilization or decomposition hasbegun. After removal from the hotplate, the vial is allowed to cool toroom temperature. The foil is removed, and the vial is extracted withdichloromethane followed by saturated aqueous NaHCO₃. The organic andaqueous extracts are shaken together, separated, and the organic extractis dried over Na₂SO₄. An aliquot of the organic solution is removed andinjected into a reverse-phase HPLC with detection by absorption of 225nm light. A drug is preferred for aerosolization where the purity of thedrug isolated by this method is greater than 85%. Such a drug has adecomposition index less than 0.15. The decomposition index is arrivedat by substracting the drug purity fraction (i.e., 0.85) from 1.

Although the invention has been described with respect to particularembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications can be made without departing from theinvention.

What is claimed is:
 1. A composition for delivery of loxapine comprisinga condensation aerosol a) wherein the condensation aerosol is formed byheating a thin film of loxapine thereof to produce a vapor, andcondensing the vapor to form a condensation aerosol comprising loxapine;b) wherein the condensation aerosol comprises particles that arecharacterized by less than 10% loxapine degradation products by weight;c) wherein the condensation aerosol has an MMAD of less than 5 microns.2. A kit for delivering a condensation aerosol, the kit comprising: a) athin film of a loxapine composition comprising loxapine, on a solidsupport, and b) a device for providing the condensation aerosol, whereinthe condensation aerosol is formed by heating the loxapine compositionto produce a vapor, and condensing the vapor to form a condensationaerosol comprising loxapine, wherein the condensation aerosol comprisesparticles that are characterized by less than 10% loxapine degradationproducts by weight, wherein the condensation aerosol has an MMAD of lessthan 5 microns.
 3. A loxapine supply article comprising: a substratehaving a surface; a layer of loxapine applied to the substrate surface,the layer of loxapine having a select thickness and a select surfacearea, the select thickness providing less than 10% degradation ofloxapine and the select surface area providing a therapeuticallyeffective loxapine dosage upon vaporization of the layer of loxapine.